history of cancer research

Milestones in Cancer Research and Discovery

During the past 250 years, we have witnessed many landmark discoveries in our efforts to make progress against cancer, an affliction known to humanity for thousands of years. This timeline shows a few key milestones in the history of cancer research.

1775: Chimney Soot & Squamous Cell Carcinoma

Percivall Pott identifies a relationship between exposure to chimney soot and the incidence of squamous cell carcinoma of the scrotum among chimney sweeps. His report is the first to clearly link an environmental exposure to the development of cancer.

1863: Inflammation & Cancer

Rudolph Virchow identifies white blood cells (leukocytes) in cancerous tissue, making the first connection between inflammation and cancer. Virchow also coins the term "leukemia" and is the first person to describe the excess number of white blood cells in the blood of patients with this disease.

1882: The First Radical Mastectomy to Treat Breast Cancer

William Halsted performs the first radical mastectomy to treat breast cancer. This surgical procedure remains the standard operation for breast cancer until the latter half of the 20th century.

1886: Inheritance of Cancer Risk

Brazilian ophthalmologist Hilário de Gouvêa provides the first documented evidence that a susceptibility to cancer can be passed on from a parent to a child. He reports that two of seven children born to a father who was successfully treated for childhood retinoblastoma, a malignant tumor of the eye, also developed the disease.

1895: The First X-Ray

Wilhelm Roentgen discovers x-rays. The first x-ray picture is an image of his wife's hand.

1898: Radium & Polonium

Marie and Pierre Curie discover the radioactive elements radium and polonium. Within a few years, the use of radium in cancer treatment begins.

1899: The First Use of Radiation Therapy to Cure Cancer

Swedish physicians Tor Stenbeck and Tage Sjogren describe the first cases of basal cell carcinoma of the skin and squamous cell carcinoma of the skin cured by X-ray therapy.

1902: Cancer Tumors & Single Cells with Chromosome Damage

Theodor Boveri proposes that cancerous tumors arise from single cells that have experienced chromosome damage and suggests that chromosome alterations cause the cells to divide uncontrollably.

1909: Immune Surveillance

Paul Ehrlich proposes that the immune system usually suppresses tumor formation, a concept that becomes known as the "immune surveillance" hypothesis. This proposal prompts research, which continues today, to harness the power of the immune system to fight cancer.

1911: Cancer in Chickens

Peyton Rous discovers a virus that causes cancer in chickens (Rous sarcoma virus), establishing that some cancers are caused by infectious agents.

1915: Cancer in Rabbits

Katsusaburo Yamagiwa and Koichi Ichikawa induce cancer in rabbits by applying coal tar to their skin, providing experimental proof that chemicals can cause cancer.

1928: The Pap Smear

George Papanicolaou discovers that cervical cancer can be detected by examining cells from the vagina under a microscope. This breakthrough leads to the development of the Pap test, which allows abnormal cervical cells to be detected and removed before they become cancerous.

1932: The Modified Radical Mastectomy for Breast Cancer

David H. Patey develops the modified radical mastectomy for breast cancer. This surgical procedure is less disfiguring than the radical mastectomy and eventually replaces it as the standard surgical treatment for breast cancer.

1937: The National Cancer Institute (NCI)

Legislation signed by President Franklin D. Roosevelt establishes the National Cancer Institute (NCI).

1937: Breast-Sparing Surgery Followed by Radiation

Sir Geoffrey Keynes describes the treatment of breast cancer with breast-sparing surgery followed by radiation therapy. After surgery to remove the tumor, long needles containing radium are inserted throughout the affected breast and near the adjacent axillary lymph nodes.

1941: Hormonal Therapy

Charles Huggins discovers that removing the testicles to lower testosterone production or administering estrogens causes prostate tumors to regress. Such hormonal manipulation—more commonly known as hormonal therapy—continues to be a mainstay of prostate cancer treatment.

1947: Antimetabolites

Sidney Farber shows that treatment with the antimetabolite drug aminopterin, a derivative of folic acid, induces temporary remissions in children with acute leukemia. Antimetabolite drugs are structurally similar to chemicals needed for important cellular processes, such as DNA synthesis, and cause cell death by blocking those processes.

1949: Nitrogen Mustard

The Food and Drug Administration (FDA) approves nitrogen mustard (mechlorethamine) for the treatment of cancer. Nitrogen mustard belongs to a class of drugs called alkylating agents, which kill cells by chemically modifying their DNA.

1950: Cigarette Smoking & Lung Cancer

Ernst Wynder, Evarts Graham, and Richard Doll identify cigarette smoking as an important factor in the development of lung cancer.

1953: The First Complete Cure of a Human Solid Tumor

Roy Hertz and Min Chiu Li achieve the first complete cure of a human solid tumor by chemotherapy when they use the drug methotrexate to treat a patient with choriocarcinoma, a rare cancer of the reproductive tissue that mainly affects women.

1958: Combination Chemotherapy

NCI researchers Emil Frei, Emil Freireich, and James Holland and their colleagues demonstrate that combination chemotherapy with the drugs 6-mercaptopurine and methotrexate can induce partial and complete remissions and prolong survival in children and adults with acute leukemia.

1960: The Philadelphia Chromosome

Peter Nowell and David Hungerford describe an unusually small chromosome in the cancer cells of patients with chronic myelogenous leukemia (CML). This chromosome, which becomes known as the Philadelphia chromosome, is found in the leukemia cells of 95% of patients with CML.

1964: A Focus on Cigarette Smoking

The U.S. Surgeon General issues a report stating that cigarette smoking is an important health hazard in the United States and that action is required to reduce its harmful effects.

1964: The Epstein-Barr virus

For the first time, a virus—the Epstein-Barr virus (EBV)—is linked to a human cancer (Burkitt lymphoma). EBV is later shown to cause several other cancers, including nasopharyngeal carcinoma, Hodgkin lymphoma, and some gastric (stomach) cancers.

1971: The National Cancer Act

On December 23, President Richard M. Nixon signs the National Cancer Act, which authorizes the NCI Director to coordinate all activities of the National Cancer Program, establish national cancer research centers, and establish national cancer control programs.

1976: The DNA of Normal Chicken Cells

Dominique Stehelin, Harold Varmus, J. Michael Bishop, and Peter Vogt discover that the DNA of normal chicken cells contains a gene related to the oncogene (cancer-causing gene) of avian sarcoma virus, which causes cancer in chickens. This finding eventually leads to the discovery of human oncogenes.

1978: Tamoxifen

FDA approves tamoxifen, an antiestrogen drug originally developed as a birth control treatment, for the treatment of breast cancer. Tamoxifen represents the first of a class of drugs known as selective estrogen receptor modulators, or SERMs, to be approved for cancer therapy.

1979: The TP53 Gene

The TP53 gene (also called p53), the most commonly mutated gene in human cancer, is discovered. It is a tumor suppressor gene, meaning its protein product (p53 protein) helps control cell proliferation and suppress tumor growth.

1984: HER2 Gene Discovered

Researchers discover a new oncogene in rat cells that they call “neu.” The human version of this gene, called HER2 (and ErbB2), is overexpressed in about 20% to 25% of breast cancers (known as HER2-positive breast cancers) and is associated with more aggressive disease and a poor prognosis.

1984: HPV 16 & 18

DNA from human papillomavirus (HPV) types 16 and 18 is identified in a large percentage of cervical cancers, establishing a link between infection with these HPV types and cervical carcinogenesis.

1985: Breast-Conserving Surgery

Results from an NCI-supported clinical trial show that women with early-stage breast cancer who were treated with breast-conserving surgery (lumpectomy) followed by whole-breast radiation therapy had similar rates of overall survival and disease-free survival as women who were treated with mastectomy alone.

1986: HER2 Oncogene Cloning

The human oncogene HER2 (also called neu and erbB2) is cloned. Overexpression of the protein product of this gene, which occurs in about 20% to 25% of breast cancers (known as HER2-positive breast cancers), is associated with more aggressive disease and a poor prognosis.

1993: Guaiac Fecal Occult Blood Testing (FOBT)

Results from an NCI-supported clinical trial show that annual screening with guaiac fecal occult blood testing (FOBT) can reduce colorectal cancer mortality by about 33%.

1994: BRCA1 Tumor Suppressor Gene Cloning

The tumor suppressor gene BRCA1 is cloned. Specific inherited mutations in this gene greatly increase the risks of breast and ovarian cancer in women and the risks of several other cancers in both men and women.

1995: BRCA2 Tumor Suppressor Gene Cloning

The tumor suppressor gene BRCA2 is cloned. Similar to BRCA1, inheriting specific BRCA2 gene mutations greatly increases the risks of breast and ovarian cancer in women and the risks of several other cancers in both men and women.

1996: Anastrozole

FDA approves anastrozole for the treatment of estrogen receptor-positive advanced breast cancer in postmenopausal women. Anastrozole is the first aromatase inhibitor (a drug that blocks the production of estrogen in the body) to be approved for cancer therapy.

1997: Rituximab

FDA approves rituximab, a monoclonal antibody, for use in patients with treatment-resistant, low-grade or follicular B-cell non-Hodgkin lymphoma (NHL). Rituximab is the first monoclonal antibody approved for use in cancer therapy. It is later approved as an initial treatment for these types of NHL, for another type of NHL called diffuse large B-cell lymphoma, and for chronic lymphocytic leukemia.

1998: NCI-Sponsored Breast Cancer Prevention Trial

Results of the NCI-sponsored Breast Cancer Prevention Trial show that the antiestrogen drug tamoxifen can reduce the incidence of breast cancer among women who are at increased risk of the disease by about 50%. FDA approves tamoxifen to reduce the incidence of breast cancer in women at increased risk.

1998: Trastuzumab

FDA approves trastuzumab, a monoclonal antibody that targets cancer cells that overexpress the HER2 gene, for the treatment of women with HER2-positive metastatic breast cancer. Trastuzumab is later approved for the adjuvant (post-operative) treatment of women with HER2-positive early-stage breast cancer.

2001: Imatinib Mesylate

Results of a clinical trial show that the drug imatinib mesylate, which targets a unique protein produced by the Philadelphia chromosome, is effective against chronic myelogenous leukemia (CML). Imatinib treatment changes the usually fatal disease into a manageable condition. Later, it is also shown to be effective in the treatment of gastrointestinal stromal tumors (GIST).

2003: NCI-Sponsored Prostate Cancer Prevention Trial (PCPT)

Results of the NCI-sponsored Prostate Cancer Prevention Trial (PCPT) show that the drug finasteride, which reduces the production of male hormones in the body, lowers a man's risk of prostate cancer by about 25%.

2006: NCI's Study of Tamoxifen and Raloxifene (STAR)

Results of NCI's Study of Tamoxifen and Raloxifene (STAR) show that postmenopausal women at increased risk of breast cancer can reduce their risk of developing the disease if they take the antiestrogen drug raloxifene. The risk of serious side effects is lower with raloxifene than with tamoxifen.

2006: Gardasil

FDA approves the human papillomavirus (HPV) vaccine Gardasil, which protects against infection by the two HPV types (HPV 16 and 18) that cause approximately 70% of all cases of cervical cancer and two additional HPV types (HPV 6 and 11) that cause 90% of genital warts. Gardasil is the first vaccine approved to prevent cervical cancer. NCI scientists made technological advances that enabled development of Gardasil and subsequent HPV vaccines.

2009: Cervarix

FDA approves Cervarix, a second vaccine that protects against infection by the two HPV types that cause approximately 70% of all cases of cervical cancer worldwide. 

2010: The First Human Cancer Treatment Vaccine

FDA approves sipuleucel-T, a cancer treatment vaccine that is made using a patient's own immune system cells (dendritic cells), for the treatment of metastatic prostate cancer that no longer responds to hormonal therapy. It is the first (and so far only) human cancer treatment vaccine to be approved.

2010: NCI-Sponsored Lung Cancer Screening Trial (NLST)

Initial results of the NCI-sponsored Lung Cancer Screening Trial (NLST) show that screening with low-dose helical computerized tomography (CT) reduced lung cancer deaths by about 20% in a large group of current and former heavy smokers.

2011: Ipilimumab

FDA approves the use of ipilimumab, a monoclonal antibody, for the treatment of inoperable or metastatic melanoma. Ipilimumab stimulates the immune system to attack cancer cells by removing a "brake" that normally controls the intensity of immune responses.

2012: NCI-Sponsored PLCO Cancer Screening Trial

Results of the NCI-sponsored PLCO Cancer Screening Trial confirm that screening people 55 years of age and older for colorectal cancer using flexible sigmoidoscopy reduces colorectal cancer incidence and mortality. In the PLCO trial, screened individuals had a 21% lower risk of developing colorectal cancer and a 26% lower risk of dying from the disease than the control subjects.

2013: Ado-Trastuzumab Emtansine (T-DM1)

FDA approves ado-trastuzumab emtansine (T-DM1) for the treatment of patients with HER2-positive breast cancer who were previously treated with trastuzumab and/or a taxane drug. T-DM1 is an immunotoxin (an antibody-drug conjugate) that is made by chemically linking the monoclonal antibody trastuzumab to the cytotoxic agent mertansine, which inhibits cell proliferation by blocking the formation of microtubules.

2014: Analyzing DNA in Cancer

Researchers from The Cancer Genome Atlas (TCGA) project, a joint effort by NCI and the National Human Genome Research Institute to analyze the DNA and other molecular changes in more than 30 types of human cancer, find that gastric (stomach) cancer is actually four different diseases, not just one, based on differing tumor characteristics. This finding from TCGA and other related projects may potentially lead to a new classification system for cancer, in which cancers are classified by their molecular abnormalities as well as their organ or tissue site of origin.

2014: Pembrolizumab

FDA approves pembrolizumab for the treatment of advanced melanoma. This monoclonal antibody blocks the activity of a protein called PD1 on immune cells, which increases the strength of immune responses against cancer.

2014: Gardasil 9

FDA approves Gardasil 9, a vaccine that protects against infection with the same four HPV types as Gardasil plus five more cancer-causing HPV types that together account for nearly 90% of cervical cancers. It is now the only HPV vaccine available in the United States.

2015: NCI-MATCH Clinical Trial

NCI and the ECOG-ACRIN Cancer Research Group launch the NCI-MATCH (Molecular Analysis for Therapy Choice) clinical trial to test more than 20 drugs and drug combinations based on molecular analysis of tumors in people with cancer. The study is designed to determine whether targeted therapies for people whose tumors have specific gene mutations will be effective regardless of their cancer type.

2015: Talimogene Laherparepvec

FDA approves talimogene laherparepvec (T-VEC) for the treatment of some patients with metastatic melanoma that cannot be surgically removed. T-VEC, the first oncolytic virus approved for clinical use, works by infecting and killing tumor cells and stimulating an immune response against cancer cells throughout the body. 

2016: Cancer Moonshot℠

Congress passes the 21st Century Cures Act, which provides funding for the Cancer Moonshot, a broad program to accelerate cancer research by investing in specific research initiatives that have the potential to transform cancer care, detection, and prevention.

2017: Pediatric MATCH

NCI and the Children’s Oncology Group launch Pediatric MATCH, an effort to extend molecular analysis and targeted treatment to children and adolescents with cancer. Like NCI-MATCH, Pediatric MATCH seeks to determine if treating tumors with molecularly targeted drugs based on the tumor’s genetic characteristics rather than the type of cancer or cancer site will be effective.

2017: CAR T-Cell Therapies

FDA approves tisagenlecleucel to treat a form of acute lymphoblastic leukemia in certain children and young adults. FDA subsequently approves axicabtagene ciloleucel for patients with large B-cell lymphomas whose cancer has progressed after receiving at least two prior treatment regimens. Both treatments are chimeric antigen receptor (CAR) T-cell therapies that are personalized for each patient. To create these therapies, T cells are removed from the patient, genetically altered to recognize cancer-specific antigens, grown to large numbers in the lab, and then infused back into the patient to stimulate their immune system to attack cancer cells.

2017: Tumor-Agnostic Approval for Pembrolizumab

FDA extends approval of pembrolizumab to treat metastatic and inoperable solid tumors that have certain genetic changes, wherever they occur in the body , that have progressed following prior treatment and that have no alternative treatment options. With this tissue-agnostic approval, pembrolizumab becomes the first cancer treatment based solely on the presence of a genetic feature in a tumor, rather than a person’s cancer type.

2017: Genomic Profiling Tests

FDA clears two products to test tumors for genetic changes that may make the tumors susceptible to treatment with FDA-approved molecularly targeted drugs. In November, FDA authorizes the MSK-IMPACT test developed and used by Memorial Sloan Kettering Cancer Center to analyze tumors for potentially actionable changes in 468 cancer-related genes. In December, FDA approves the FoundationOne CDx test, which evaluates genetic changes in 324 genes known to fuel cancer growth. The FoundationOne test serves as a companion diagnostic for several FDA-approved drugs targeting five common types of cancer.

2018: TCGA PanCancer Atlas

NIH-funded researchers with TCGA complete an in-depth genomic analysis of 33 cancer types. The PanCancer Atlas provides a detailed genomic analysis of molecular and clinical data from more than 10,000 tumors that gives cancer researchers an unprecedented understanding of how, where, and why tumors arise in humans. 

2018: NCI-Sponsored TAILORx Clinical Trial

Results from the NCI-sponsored Trial Assigning IndividuaLized Options for Treatment (Rx), or TAILORx, clinical trial show that most women with early-stage breast cancer do not benefit from having chemotherapy after surgery. The trial used a molecular test that assesses the expression of 21 genes associated with breast cancer recurrence to assign women with early-stage, hormone receptor–positive, HER2-negative breast cancer that hasn’t spread to the lymph nodes to the most appropriate and effective post-operative treatment. It is one of the first trials to examine a way to personalize cancer treatment

2018: Larotrectinib

FDA approves larotrectinib, the first drug that targets tumors with NTRK gene fusions. The approval is for pediatric or adult patients with metastatic or inoperable solid tumors that have worsened after previous treatment anywhere in the body driven by an NTRK gene fusion without a known acquired resistance mutation. Larotrectinib is the second drug approved to treat cancer with specific molecular features regardless of where the cancer is located.

2020: International Pan-Cancer Analysis of Whole Genomes

A consortium of international researchers analyzes more than 2,600 whole genomes from 38 types of cancer and matching normal tissues to identify common patterns of molecular changes. The Pan-Cancer Analysis of Whole Genomes study, which used data collected by the International Cancer Genome Consortium and TCGA, uncovers the complex role that changes throughout the genome play in cancer development, growth, and spread. The study also extends genomic analyses of cancer beyond the protein-coding regions to the complete genetic composition of cells.  

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The History of Cancer: Discovery and Treatment

History of cancer.

• Modern Advances

Frequently Asked Questions

Cancer may have been “discovered” and written about thousands of years ago. However, the disease itself has actually existed since before the evolution of humans.

It was first documented in Egypt about 5,000 years ago. Since that time, people from cultures all over the world have written about the disease and its potential treatments.

This article will look at what we know about the history of cancer. It will also talk about how our understanding of what causes cancer and how it can be treated has changed over time.

• 3000 BCE : The world’s earliest known mention of cancer was found in a papyrus document from ancient Egypt. It described tumors found in the breast . The cancer was treated by destroying the tissue with a hot instrument called “the fire drill”—a technique we now call “cauterization.” Some writings have shown that the ancient Egyptians could distinguish between cancerous (malignant) and noncancerous (benign) tumors.
• 460 BCE : In ancient Greece, Hippocrates thought there were four fluids in the body that influenced health: blood, phlegm , yellow bile , and black bile. He believed that having too much black bile in a part of the body caused cancer. For the next 1,400 years, people believed cancer was caused by too much black bile.
• 1628 : William Harvey, physician to King James I of England, dissected animals and human cadavers to learn more about how the body worked. When he published a book about the circulatory system, it upended ancient ideas and opened the door for more research on the workings of the human body.
• 1761 : Giovanni Morgagni of Padua published a book based on hundreds of autopsies he had performed on former patients of his, looking at both their clinical symptoms in life and his postmortem observations of their organs. This laid the groundwork for modern autopsies to determine the cause of someone’s death.
• 1775: A British surgeon named Percivall Pott discovered that testicular cancer was common in chimney sweeps. This was the first time a cancer was connected to an environmental cause.
• 17th century : The discovery of the lymphatic system led to new ideas about cancer. The lymphatic system includes the tissues, vessels, and organs that move a substance called lymph around your body. Lymph is an important part of your immune system. When the lymphatic system was discovered, it brought about the possibility that problems in this part of the body could cause cancer. This idea was called the lymph theory. It replaced Hippocrates’ theory about black bile and cancer.
• 1838 : Johannes Mueller, a German pathologist, showed that cancer is made of cells, not lymph. Mueller’s student, physician Rudolf Virchow, figured out that all our cells—even cancerous ones—come from other cells. However, he thought cancer spread in the body “like a liquid.”
• 1860 : A German surgeon named Karl Thiersch was the first person to prove that cancer spread through malignant cells.

How Cancer Was Named

Although most people cite Hippocrates as the first person to use the word cancer, he actually used the Greek words karkinos and karkinoma when he wrote about tumors. These words were related to the Greek word for “crab” because Hippocrates thought the insides of the tumors looked like crabs.

The Roman physician Celsus was the first to translate the word into the Latin word “cancer.”

20th Century to Present Day

The 20th century was an exciting time in cancer research. Carcinogens,  chemotherapy , radiation therapy, and better ways to diagnose cancer were all discovered in these years. Some of the most important discoveries of the 20th century include:

• 1915 : Katsusaburo Yamagiwa and Koichi Ichikawa at Tokyo University applied coal tar to the skin of rabbits, inducing cancer and showing that some substances are carcinogens or cancer-causing.
• 1962 : James Watson and Frances Crick won a Nobel Prize for discovering the chemical structure of DNA.
• 1970s : Scientists discover oncogenes and tumor suppressor genes.
• 1981: Japanese professor Takeshi Hirayama published the first research linking lung cancer to second-hand smoke.  
• 1982: Baruch S. Blumberg helped develop a vaccine against hepatitis B, a cause of liver cancer.
• 1989: The first gene therapy cancer treatments began to evolve.
• 1994: Scientists discovered the BRCA1 gene. This was the first known gene found to predispose a person to developing breast or ovarian cancer.
• 1999: Jan Walboomers and Michele Manos found evidence implicating human papillomavirus (HPV) to 99.7% percent of cervical cancers.

Today, we are still learning more about cancer. We have found ways to prevent and treat some forms of cancer and even cure others. Clinical trials have allowed scientists to test new ways to find and treat cancer. Some of this century’s notable discoveries so far include:

• 2006: The first vaccine against the HPV virus was approved in the United States.
• 2009: Researchers find that immunotherapy improves cure rates for children with neuroblastoma.
• 2011: Low-dose computed tomography (CT) scans help reduce lung cancer deaths by finding early-stage cancer in high-risk people.
• 2016: Researchers find evidence that a type of gene therapy called (CAR) T can produce remission in some people with B-cell hematologic cancers.
• 2021: The OncoKB, a genetic variant database, was recognized by the FDA as a tool for predicting drug responses in people with cancer. This will help oncologists find the best individual treatments for people with specific types of cancer.

Humans have known about cancer for millennia, but our modern understanding of cancer has only developed in the past few centuries. New advancements are being made all the time, and huge leaps have been made in the last few decades alone. This bodes well for the future of cancer treatments and therapies.

A Word From Verywell

How we look at cancer and its treatments has significantly changed in the last few centuries. Even decades ago, we had limited treatment options and less research. Learning about cancer and treatment history can be interesting when seeing how far we’ve come in such a short time. With new research and discoveries occurring all the time, the future of cancer research is an exciting topic.

Cancer has been around since humanity began recording its history and likely existed even before that time. The oldest description of cancer originates from Egypt around 3000 BC in a text called the Edwin Smith Papyrus, which also describes the Egyptian process of tumor removal using a method of cauterization.

Cancer was treated throughout most of the 1800s using surgery to remove cancerous tumors and affected organs. The discovery of X-rays in 1895 by a physicist named Wilhelm Konrad Roentgen helped to diagnose cancer cases and helped pave the way for radiation therapy.

In 1838, a pathologist known as Johannes Müller showed that cancer cells are what make up cancer. Before this, it was believed that cancer was made up of lymph.

It was first treated by surgery, although early physicians realized that cancer often came back after surgery.

The German chemist Paul Ehrlich started working with drugs to treat infectious diseases in the early 1900s. He coined the term “chemotherapy” to describe the use of chemicals to treat disease. He wasn’t very optimistic about medicine to treat cancer, though.

Cancer is more common with age, and more people are living longer, increasing the risk of cancer. A better metric of progress is the cancer death rate, which is decreasing, indicating that we are developing better treatments for cancer.

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Handbook of Oncobiology: From Basic to Clinical Sciences pp 1–29 Cite as

History, Evolution, Milestones in Cancer Research and Treatment

• Indu Sharma   ORCID: orcid.org/0000-0001-9846-9787 4 ,
• Anuradha Sharma   ORCID: orcid.org/0000-0001-5975-1456 4 ,
• Reena Tomer   ORCID: orcid.org/0000-0003-1133-763X 4 ,
• Neha Negi   ORCID: orcid.org/0000-0002-1902-7081 4 &
• Ranbir Chander Sobti 5  
• Living reference work entry
• First Online: 15 July 2023

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The historical findings of patients with cancer from ancient Egyptian and Greek civilizations support the millennium long medical history of cancer. However, the disease at that time was mostly treated with not so effective radical surgery and cautery, making death the ultimate outcome of cancer patients. Over the centuries, various breakthrough discoveries have not only reformed the cancer detection but also contributed to the development of more effective therapeutic approaches. The most significant of them was the unearthing of cytotoxic antitumor drugs and the inception of chemotherapy. Since then, an exponential progress has been witnessed over the time about new cancer drugs. Another revolution in the field of oncology was targeted therapy with the development of specific drugs for some molecular targets involved in vital neoplastic processes. Collectively, chemotherapy and targeted therapy have definitely enhanced not only the survival rate but also the quality of life of cancer patients. In present times, genetic engineering studies have amplified the further advancements of cancer biology by utilizing monoclonal antibodies and immune checkpoint inhibitors specifically for advanced or metastatic tumors. Hence, cancer research has continuously grown with an intend to develop newer and better therapeutic approaches for cancer. Most recent, artificial intelligence and precision medicine are certainly going to bring a new revolution in the field of medical oncology.

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Sharma, I., Sharma, A., Tomer, R., Negi, N., Sobti, R.C. (2023). History, Evolution, Milestones in Cancer Research and Treatment. In: Sobti, R.C., Ganguly, N.K., Kumar, R. (eds) Handbook of Oncobiology: From Basic to Clinical Sciences. Springer, Singapore. https://doi.org/10.1007/978-981-99-2196-6_2-1

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• Open access
• Published: 05 February 2020

The evolutionary history of 2,658 cancers

• Moritz Gerstung 1 , 2 , 3   na1 ,
• Clemency Jolly 4   na1 ,
• Ignaty Leshchiner 5   na1 ,
• Stefan C. Dentro 3 , 4 , 6   na1 ,
• Santiago Gonzalez 1   na1 ,
• Daniel Rosebrock 5 ,
• Thomas J. Mitchell 3 , 7 ,
• Yulia Rubanova 8 , 9 ,
• Pavana Anur 10 ,
• Kaixian Yu 11 ,
• Maxime Tarabichi 3 , 4 ,
• Amit Deshwar 8 , 9 ,
• Jeff Wintersinger 8 , 9 ,
• Kortine Kleinheinz 12 , 13 ,
• Ignacio Vázquez-García 3 , 7 ,
• Kerstin Haase 4 ,
• Lara Jerman 1 , 14 ,
• Subhajit Sengupta 15 ,
• Geoff Macintyre 16 ,
• Salem Malikic 17 , 18 ,
• Nilgun Donmez 17 , 18 ,
• Dimitri G. Livitz 5 ,
• Marek Cmero 19 , 20 ,
• Jonas Demeulemeester 4 , 21 ,
• Steven Schumacher 5 ,
• Yu Fan 11 ,
• Xiaotong Yao 22 , 23 ,
• Juhee Lee 24 ,
• Matthias Schlesner 12 ,
• Paul C. Boutros 8 , 25 , 26 ,
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• Ville Mustonen 35 ,
• Ke Yuan 16 , 36 ,
• Wenyi Wang 11 ,
• Quaid D. Morris 8 , 9 ,
• PCAWG Evolution & Heterogeneity Working Group ,
• Paul T. Spellman 10   na2 ,
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• Cancer genomics
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An Author Correction to this article was published on 25 January 2023

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Cancer develops through a process of somatic evolution 1 , 2 . Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes 3 . Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) 4 , we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.

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Evolutionary signatures of human cancers revealed via genomic analysis of over 35,000 patients

Diletta Fontana, Ilaria Crespiatico, … Daniele Ramazzotti

Pan-cancer analysis of whole genomes

The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium

The repertoire of mutational signatures in human cancer

Ludmil B. Alexandrov, Jaegil Kim, … PCAWG Consortium

Similar to the evolution in species, the approximately 10 14 cells in the human body are subject to the forces of mutation and selection 1 . This process of somatic evolution begins in the zygote and only comes to rest at death, as cells are constantly exposed to mutagenic stresses, introducing 1–10 mutations per cell division 2 . These mutagenic forces lead to a gradual accumulation of point mutations throughout life, observed in a range of healthy tissues 5 , 6 , 7 , 8 , 9 , 10 , 11 and cancers 12 . Although these mutations are predominantly selectively neutral passenger mutations, some are proliferatively advantageous driver mutations 13 . The types of mutation in cancer genomes are well studied, but little is known about the times when these lesions arise during somatic evolution and where the boundary between normal evolution and cancer progression should be drawn.

Sequencing of bulk tumour samples enables partial reconstruction of the evolutionary history of individual tumours, based on the catalogue of somatic mutations they have accumulated 3 , 14 , 15 . These inferences include timing of chromosomal gains during early somatic evolution 16 , phylogenetic analysis of late cancer evolution using matched primary and metastatic tumour samples from individual patients 17 , 18 , 19 , 20 , and temporal ordering of driver mutations across many samples 21 , 22 .

The PCAWG Consortium has aggregated whole-genome sequencing data from 2,658 cancers 4 , generated by the ICGC and TCGA, and produced high-accuracy somatic variant calls, driver mutations, and mutational signatures 4 , 23 , 24 (Methods and Supplementary Information ).

Here, we leverage the PCAWG dataset to characterize the evolutionary history of 2,778 cancer samples from 2,658 unique donors across 38 cancer types. We infer timing and patterns of chromosomal evolution and learn typical sequences of mutations across samples of each cancer type. We then define broad periods of tumour evolution and examine how drivers and mutational signatures vary between these epochs. Using clock-like mutational processes, we map mutation timing estimates into approximate real time. Combined, these analyses allow us to sketch out the typical evolutionary trajectories of cancer, and map them in real time relative to the point of diagnosis.

Reconstructing the life history of tumours

The genome of a cancer cell is shaped by the cumulative somatic aberrations that have arisen during its evolutionary past, and part of this history can be reconstructed from whole-genome sequencing data 3 (Fig. 1a ). Initially, each point mutation occurs on a single chromosome in a single cell, which gives rise to a lineage of cells bearing the same mutation. If that chromosomal locus is subsequently duplicated, any point mutation on this allele preceding the gain will subsequently be present on the two resulting allelic copies, unlike mutations succeeding the gain, or mutations on the other allele. As sequencing data enable the measurement of the number of allelic copies, one can define categories of early and late clonal variants, preceding or succeeding copy number gains, as well as unspecified clonal variants, which are common to all cancer cells, but cannot be timed further. Lastly, we identify subclonal mutations, which are present in only a subset of cells and have occurred after the most recent common ancestor (MRCA) of all cancer cells in the tumour sample ( Supplementary Information ).

a , Principles of timing mutations and copy number gains based on whole-genome sequencing. The number of sequencing reads reporting point mutations can be used to discriminate variants as early or late clonal (green or purple, respectively) in cases of specific copy number gains, as well as clonal (blue) or subclonal (red) in cases without. b , Annotated point mutations in one sample based on VAF (top), copy number (CN) state and structural variants (middle), and resulting timing estimates (bottom). LOH, loss of heterozygosity. c , Overview of the molecular timing distribution of copy number gains across cancer types. Pie charts depict the distribution of the inferred mutation time for a given copy number gain in a cancer type. Green denotes early clonal gains, with a gradient to purple for late gains. The size of each chart is proportional to the recurrence of this event. Abbreviations for each cancer type are defined in  Supplementary Table 1 . d , Heat maps representing molecular timing estimates of gains on different chromosome arms ( x axis) for individual samples ( y axis) for selected tumour types. e , Temporal patterns of two near-diploid cases illustrating synchronous gains (top) and asynchronous gains (bottom). f , Left, distribution of synchronous and asynchronous gain patterns across samples, split by WGD status. Uninformative samples have too few or too small gains for accurate timing. Right, the enrichment of synchronous gains in near-diploid samples is shown by systematic permutation tests. g , Proportion of copy number segments ( n  = 90,387) with secondary gains. Error bars denote 95% credible intervals. ND, near diploid. h , Distribution of the relative latency of n  = 824 secondary gains with available timing information, scaled to the time after the first gain and aggregated per chromosome.

Source data

The ratio of duplicated to non-duplicated mutations within a gained region can be used to estimate the time point when the gain happened during clonal evolution, referred to here as molecular time, which measures the time of occurrence relative to the total number of (clonal) mutations. For example, there would be few, if any, co-amplified early clonal mutations if the gain had occurred right after fertilization, whereas a gain that happened towards the end of clonal tumour evolution would contain many duplicated mutations 14 (Fig. 1a , Methods).

These analyses are illustrated in Fig. 1b . As expected, the variant allele frequencies (VAFs) of somatic point mutations cluster around the values imposed by the purity of the sample, local copy number configuration and identified subclonal populations. The depicted clear cell renal cell carcinoma has gained chromosome arm 5q at an early molecular time as part of an unbalanced translocation t(3p;5q), which confirms the notion that this lesion often occurs in adolescence in this cancer type 16 . At a later time point, the sample underwent a whole genome duplication (WGD) event, duplicating all alleles, including the derivative chromosome, in a single event, as evidenced by the mutation time estimates of all copy number gains clustering around a single time point, independently of the exact copy number state.

Timing patterns of copy number gains

To systematically examine the mutational timing of chromosomal gains throughout the evolution of tumours in the PCAWG dataset, we applied this analysis to the 2,116 samples with copy number gains suitable for timing ( Supplementary Information ). We find that chromosomal gains occur across a wide range of molecular times (median molecular time 0.60, interquartile range (IQR) 0.10–0.87), with systematic differences between tumour types, whereas within tumour types, different chromosomes typically show similar distributions (Fig. 1c , Extended Data Figs. 1 , 2 , Supplementary Information ). In glioblastoma and medulloblastoma, a substantial fraction of gains occurs early in molecular time. By contrast, in lung cancers, melanomas and papillary kidney cancers, gains arise towards the end of the molecular timescale. Most tumour types, including breast, ovarian and colorectal cancers, show relatively broad periods of chromosomal instability, indicating a very variable timing of gains across samples.

There are, however, certain tumour types with consistently early or late gains of specific chromosomal regions. Most pronounced is glioblastoma, in which 90% of tumours contain single copy gains of chromosome 7, 19 or 20 (Fig. 1c, d ). Notably, these gains are consistently timed within the first 10% of molecular time, which suggests that they arise very early in a patient’s lifetime. In the case of trisomy 7, typically less than 3 out of 600 single nucleotide variants (SNVs) on the whole chromosome precede the gain (Extended Data Fig. 3a, b ). On the basis of a mutation rate of µ  = 4.8 × 10 −10 to 3.0 × 10 −9 SNVs per base pair per division 25 , this indicates that the trisomy occurs within the first 6–39 cell divisions, suggesting a possible early developmental origin, in agreement with somatic mosaicisms observed in the healthy brain 26 . Similarly, the duplications leading to isochromosome 17q in medulloblastoma are timed exceptionally early (Extended Data Fig. 3c, d ).

Notably, we observed that gains in the same tumour often appear to occur at a similar molecular time, pointing towards punctuated bursts of copy number gains involving most gained segments (Fig. 1e ). Although this is expected in tumours with WGD (Fig. 1b ), it may seem surprising to observe synchronous gains in near-diploid tumours, particularly as only 6% of co-amplified chromosomal segments were linked by a direct inter-chromosomal structural variant. Still, synchronous gains are frequent, occurring in 57% (468 out of 815) of informative near-diploid tumours, 61% more frequently than expected by chance ( P  < 0.01, permutation test; Fig. 1f ). Because most arm-level gains increment the allele-specific copy number by 1 (80–90%; Fig. 1g ), it seems that these gains arise through mis-segregation of single copies during anaphase. This notion is further supported by the observation that in about 85% of segments with two gains of the same allele, the second gain appears with noticeable latency after the first (Fig. 1h ). Therefore, the extensive chromosome-scale copy number aberrations observed in many cancer genomes are seemingly caused by a limited number of events—possibly by merotelic attachments of chromosomes to multipolar mitotic spindles 27 , or as a consequence of negative selection of individual aneuploidies 28 —offering an explanation for observations of punctuated evolution in breast and colorectal cancer 29 , 30 .

Timing of point mutations in driver genes

As outlined above, point mutations (SNVs and insertions and deletions (indels)) can be qualitatively assigned to different epochs, allowing the timing of driver mutations. Out of the 47 million point mutations in 2,583 unique samples, 22% were early clonal, 7% late clonal, 53% unspecified clonal and 17% subclonal (Fig. 2a ). Among a panel of 453 cancer driver genes, 5,913 oncogenic point mutations were identified 4 , of which 29% were early clonal, 5% late clonal, 56% unspecified clonal and 8% subclonal. It thus emerges that common drivers are enriched in the early clonal and unspecified clonal categories and depleted in the late clonal and subclonal ones, indicating a preferential early timing (Fig. 2b ). For example, driver mutations in TP53 and KRAS are 12 and 8 times enriched in early clonal stages, respectively. For TP53 , this trend is independent of tumour type (Fig. 2c ). Mutations in PIK3CA are two times more frequently clonal than expected, and non-coding changes near the TERT gene are three times more frequently early clonal.

a , Top, distribution of point mutations over different mutation periods in n  = 2,778 samples. Middle, timing distribution of driver mutations in the 50 most recurrent lesions across n  = 2,583 white listed samples from unique donors. Bottom, distribution of driver mutations across cancer types; colour as defined in the inset. b , Relative timing of the 50 most recurrent driver lesions, calculated as the odds ratio of early versus late clonal driver mutations versus background, or clonal versus subclonal. Error bars denote 95% confidence intervals derived from bootstrap resampling. Odds ratios overlapping 1 in less than 5% of bootstrap samples are considered significant (coloured). The underlying number of samples with a given mutation is shown in a . c , Relative timing of TP53 mutations across cancer types, as in b . The number of samples is defined in the x -axis labels. d , Estimated number of unique lesions (genes) contributing 50% of all driver mutations in different timing epochs across n  = 2,583 unique samples, containing n  = 5,756 driver mutations with available timing information. Error bars denote the range between 0 and 1 pseudocounts; bars denote the average of the two values. NA, not applicable; NS, not significant.

Aggregating the clonal status of all driver point mutations over time reveals an increased diversity of driver genes mutated at later stages of tumour development: 50% of all early clonal driver mutations occur in just 9 genes, whereas 50% of late and subclonal mutations occur in approximately 35 different genes each, a nearly fourfold increase (Fig. 2d ). Consistent with previous studies of individual tumour types 31 , 32 , 33 , 34 , these results suggest that, in general, the very early events in cancer evolution occur in a constrained set of common drivers, and a more diverse array of drivers is involved in late tumour development.

Relative timing of somatic driver events

Although timing estimates of individual events reflect evolutionary periods that differ from one sample to another, they define in part the order in which driver mutations and copy number alterations have occurred in each sample (Fig. 3a–d ). As confirmed by simulations, aggregating these orderings across samples defines a probabilistic ranking of lesions (Fig. 3a ), recapitulating whether each mutation occurs preferentially early or late during tumour evolution (Extended Data Figs. 4 , 5 , Supplementary Information ).

a , Schematic representation of the ordering process. b – d , Examples of individual patient trajectories (partial ordering relationships), the constituent data for the ordering model process. e – g , Preferential ordering diagrams for colorectal adenocarcinoma (ColoRect–AdenoCA) ( e ), pancreatic neuroendocrine cancer (Panc–Endocrine) ( f ) and glioblastoma (CNS–GBM) ( g ). Probability distributions show the uncertainty of timing for specific events in the cohort. Events with odds above 10 (either earlier or later) are highlighted. The prevalence of the event type in the cohort is displayed as a bar plot on the right.

In colorectal adenocarcinoma, for example, we find APC mutations to have the highest odds of occurring early, followed by KRAS , loss of 17p and TP53 , and SMAD4 (Fig. 3b , e). Whole-genome duplications occur after tumours have accumulated several driver mutations, and many chromosomal gains and losses are typically late. These results are in agreement with the classical APC-KRAS-TP53 progression model of Fearon and Vogelstein 35 , but add considerable detail.

In many cancer types, the sequence of events during cancer progression has not previously been determined in detail. For example, in pancreatic neuroendocrine cancers, we find that many chromosomal losses, including those of chromosomes 2, 6, 11 and 16, are among the earliest events, followed by driver mutations in MEN1 and DAXX (Fig. 3c, f ). WGD events occur later, after many of these tumours have reached a pseudo-haploid state due to widespread chromosomal losses. In glioblastoma, we find that the loss of chromosome 10, and driver mutations in TP53 and EGFR are very early, often preceding early gains of chromosomes 7, 19 and 20 (Fig. 3d, g ). Mutations in the TERT promoter tend to occur at early to intermediate time points, whereas other driver mutations and copy number changes tend to be later events.

Across cancer types, we typically find TP53 mutations among the earliest events, as well as losses of chromosome 17 ( Supplementary Information ). WGD events usually have an intermediate ranking, and most copy number changes occur later. Losses typically precede gains, and consistent with the results above, common drivers typically occur before rare drivers.

Timing of mutational signatures

The cancer genome is shaped by various mutational processes over its lifetime, stemming from exogenous and cell-intrinsic DNA damage, and error-prone DNA replication, leaving behind characteristic mutational spectra, termed mutational signatures 24 , 36 . Stratifying mutations by their clonal allelic status, we find evidence for a changing mutational spectrum between early and late clonal time points in 29% (530 out of 1,852) of informative samples ( P  < 0.05, Bonferroni-adjusted likelihood-ratio test), typically changing the spectrum by 19% (median absolute difference; range 4–66%) (Fig. 4a, b , Extended Data Fig. 6 ). Similarly, 30% of informative samples (729 out of 2,387) displayed changes of their mutation spectrum between the clonal and subclonal state, with median difference of 21% (range 3–72%). Combined, the mutation spectrum changes throughout tumour evolution in 40% of samples (1,069 out of 2,688).

a , Example of tumours with substantial changes between mutation spectra of early (left) and late (right) clonal time points. The attribution of mutations to the most characteristic signatures are shown. b , Example of clonal-to-subclonal mutation spectrum change. c , Fold changes between relative proportions of early and late clonal mutations attributed to individual mutational signatures. Points are coloured by tissue type. Data are shown for samples ( n  = 530) with measurable changes in their overall mutation spectra and restricted to signatures active in at least 10 samples. Box plots demarcate the first and third quartiles of the distribution, with the median shown in the centre and whiskers covering data within 1.5× the IQR from the box. d , Fold changes between clonal and subclonal periods in samples ( n  = 729) with measurable changes in their mutation spectra, analogous to c .

To quantify whether the observed temporal changes can be attributed to known and suspected mutational processes, we decomposed the mutational spectra at each time point into a catalogue of 57 mutational signatures, including double base substitution and indel signatures 24 (Methods).

In general, these mutational signatures display a predominantly undirected temporal variability over several orders of magnitude (Fig. 4c, d , Extended Data Fig. 7 ). In addition, several signatures demonstrate distinct temporal trends. As one may expect, signatures of exogenous mutagens are predominantly active in the early clonal stages of tumorigenesis. These include tobacco smoking in lung adenocarcinoma (signature SBS4, median fold change 0.43, IQR 0.31–0.72), consistent with previous reports 37 , 38 , and ultraviolet light exposure in melanoma (SBS7; median fold change 0.16, IQR 0.09–0.43). Another strong decrease over time is found for a signature of unknown aetiology, SBS12, which acts mostly in liver cancers (median fold change 0.22, IQR 0.06–0.41). In chronic lymphoid leukaemia, there was a 20-fold relative decrease in mutations associated with somatic hypermutation (SBS9; median fold change 0.05, IQR 0.02–0.43) from clonal to subclonal stages.

Some mutational processes tend to increase throughout cancer evolution. For example, we see that APOBEC mutagenesis (SBS2 and SBS13) increases in many cancer types from the early to late clonal stages (median fold change 2.0, IQR 0.8–3.6), as does a newly described signature SBS38 (median fold 3.6, IQR 1.8–11). Signatures of defective mismatch repair (SBS6, 14, 15, 20, 21, 26 and 44) increase from clonal to subclonal stages (median fold 1.8, IQR 1.2–3.0).

Chronological time estimates

The molecular timing data presented above do not measure the occurrence of events in chronological time. If the rate at which mutations are acquired per year in each sample was constant, the chronological time would simply be the product of the estimated molecular timing and age at diagnosis. However, this relation will be nonlinear if the mutation rate changes over time, and is inflated by acquired mutational processes, as suggested by the analysis in the previous section. Some of these issues can be mitigated by counting only mutations contributed by endogenous and less variable mutational processes, such as CpG-to-TpG mutations (hereafter CpG>TpG) caused by spontaneous deamination of 5-methyl-cytosine to thymine at CpG dinucleotides, which have been proposed as a molecular clock 12 . Our supplementary analysis suggests that, although the baseline CpG>TpG mutation rate in cancers is very close to that in normal cells, there appears to be a moderate increase (1–10 times, adding between 20 and 40% of mutations) in cancers (Extended Data Fig. 8 ). As this shifts chronological timing estimates, we model different scenarios of the evolution of the CpG>TpG mutation rate (Fig. 5a ).

a , Mapping of molecular timing estimates to chronological time under different scenarios of increases in the CpG>TpG mutation rate. A greater increase before diagnosis indicates an inflation of the mutation timescale. b , Median latency between WGDs and the last detectable subclone before diagnosis under different scenarios of CpG>TpG mutation rate increases for n  = 569 non-hypermutant cancers with at least 100 informative SNVs, low tumour in normal contamination and at least five samples per tumour histology. c , Median latency between the MRCA and the last detectable subclone before diagnosis for different CpG>TpG mutation rate changes in n  = 1,921 non-hypermutant samples with low tumour in normal contamination and at least 5 cases per cancer type.

Applying this logic to time WGDs, which yield sufficient numbers of CpG>TpG mutations, demonstrates that they occur several years and possibly even a decade or more before diagnosis in some cancer types, under a range of scenarios of mutation rate increase (Fig. 5b , Extended Data Fig. 9 ). A notable example is ovarian adenocarcinoma, which appears to have a median latency of more than 10 years. This holds true even under a scenario of a CpG>TpG rate increase of 20-fold, which would be far beyond the 7.5-fold rate increase observed in matched primary and relapse samples 39 (Extended Data Fig. 8f ). Notably, these results suggest WGD may occur throughout the entire female reproductive life (Extended Data Fig. 9b ). The latency between the MRCA and the last detectable subclone is shorter, typically several months to years (Fig. 5c ).

These timescales of cancer evolution are further supported by the fact that progression of most known precancerous lesions to carcinomas usually spans many years, if not decades 40 , 41 , 42 , 43 , 44 , 45 . Our data corroborate these timescales and extend them to cancer types without detectable premalignant conditions, raising the hope that these tumours could also be detected in less malignant stages.

To our knowledge, our study presents the first large-scale genome-wide reconstruction of the evolutionary history of cancers, reconstructing both early (pre-cancer) and later stages of 38 cancer types. This is facilitated by the timing of copy number gains relative to all other events in the genome, through multiplicity and clonal status of co-amplified point mutations. However, several limitations exist ( Supplementary Information ). Perhaps most importantly, molecular timing is based on point mutations and is therefore subject to changes in mutation rate. Notably, healthy tissues acquire point mutations at rates not too dissimilar from those seen in cancers, particularly when considering only endogenous mutational processes, and furthermore, some tissues are riddled with microscopic clonal expansions of driver gene mutations 5 , 6 , 7 , 8 , 9 , 11 . This is direct evidence that the life history of almost every cell in the human body, including those that develop into cancer, is driven by somatic evolution.

Together, the data presented here enable us to draw approximate timelines summarizing the typical evolutionary history of each cancer type (Fig. 6 , Supplementary Information for all other cancer types). These make use of the qualitative timing of point mutations and copy number alterations, as well as signature activities, which can be interleaved with the chronological estimates of WGD and the appearance of the MRCA.

a – d , Timelines representing the length of time, in years, between the fertilized egg and the median age of diagnosis for colorectal adenocarcinoma ( a ), squamous cell lung cancer ( b ), ovarian adenocarcinoma ( c ) and pancreatic adenocarcinoma ( d ). Real-time estimates for major events, such as WGD and the emergence of the MRCA, are used to define early, variable, late and subclonal stages of tumour evolution approximately in chronological time. The range of chronological time estimates according to varying clock mutation acceleration rates is shown as well, with tick marks corresponding to 1×, 2.5×, 5×, 7.5×, 10× and 20×. Driver mutations and copy number alterations (CNA) are shown in each stage according to their preferential timing, as defined by relative ordering. Mutational signatures (Sigs) that, on average, change over the course of tumour evolution, or are substantially active but not changing, are shown in the epoch in which their activity is greatest. DBS, double base substitution; SBS, single base substitutions. Where applicable, lesions with a known timing from the literature are annotated; dagger symbols denotes events that were found to have a different timing; asterisk symbol denotes events that agree with our timing.

It is remarkable that the evolution of practically all cancers displays some level of order, which agrees very well with, and adds much detail to, established models of cancer progression 35 , 46 . For example, TP53 with accompanying 17p deletion is one of the most frequent initiating mutations in a variety of cancers, including ovarian cancer, in which it is the hallmark of its precancerous precursor lesions 47 . Furthermore, the list of typically early drivers includes most other highly recurrent cancer genes, such as KRAS , TERT and CDKN2A , indicating a preferred role in early and possibly even pre-cancer evolution. This initially constrained set of genes broadens at later stages of cancer development, suggesting an epistatic fitness landscape canalizing the first steps of cancer evolution. Over time, as tumours evolve, they follow increasingly diverse paths driven by individually rare driver mutations, and by copy number alternations. However, none of these trends is absolute, and the evolutionary paths of individual tumours are highly variable, showing that cancer evolution follows trends, but is far from deterministic.

Our study sheds light on the typical timescales of in vivo tumour development, with initial driver events seemingly occurring up to decades before diagnosis, demonstrating how cancer genomes are shaped by a lifelong process of somatic evolution, with fluid boundaries between normal ageing processes 5 , 6 , 7 , 8 , 9 , 10 , 11 and cancer evolution. Nevertheless, the presence of genetic aberrations with such long latency raises hopes that aberrant clones could be detected early, before reaching their full malignant potential.

The PCAWG series consists of 2,778 tumour samples (2,703 white listed, 75 grey listed) from 2,658 donors. All samples in this dataset underwent whole-genome sequencing (minimum average coverage 30× in the tumour, 25× in the matched normal samples), and were processed with a set of project-specific pipelines for alignment, variant calling, and quality control 4 . Copy number calls were established by combining the output of six individual callers into a consensus using a multi-tier approach, resulting in a copy number profile, a purity and ploidy value and whether the tumour has undergone a WGD ( Supplementary Information ). Consensus subclonal architectures have been obtained by integrating the output of 11 subclonal reconstruction callers, after which all SNVs, indels and structural variants are assigned to a mutation cluster using the MutationTimer.R approach ( Supplementary Information ). Driver calls have been defined by the PCAWG Driver Working Group 4 , and mutational signatures are defined by the PCAWG Signatures Working Group 24 . A more detailed description can be found in  Supplementary Information, section 1 .

Data accrual was based on sequencing experiments performed by individual member groups of the ICGC and TCGA, as described in an associated study 4 . As this is a meta-analysis of existing data, power calculations were not performed and the investigators were not blinded to cancer diagnoses.

Timing of gains

We used three related approaches to calculate the timing of copy number gains (see  Supplementary Information, section 2 ). In brief, the common feature is that the expected VAF of a mutation ( E ) is related to the underlying number of alleles carrying a mutation according to the formula: E [ X ] =  nmfρ /[ N (1 −  ρ ) +  Cρ ], in which X is the number of reads, n denotes the coverage of the locus, the mutation copy number m is the number of alleles carrying the mutation (which is usually inferred), f is the frequency of the clone carrying the given mutation ( f  = 1 for clonal mutations). N is the normal copy number (2 on autosomes, 1 or 2 for chromosome X and 0 or 1 for chromosome Y), C is the total copy number of the tumour, and ρ is the purity of the sample.

The number of mutations n m  at each allelic copy number m  then informs about the time when the gain has occurred. The basic formulae for timing each gain are, depending on the copy number configuration:

in which 2 + 1 refers to major and minor copy number of 2 and 1, respectively. Methods differ slightly in how the number of mutations present on each allele are calculated and how uncertainty is handled ( Supplementary Information ).

Timing of mutations

The mutation copy number m and the clonal frequency f is calculated according to the principles indicated above. Details can be found in  Supplementary Information, section 2 . Mutations with f  = 1 are denoted as ‘clonal’, and mutations with f < 1 as ‘subclonal’. Mutations with f  = 1 and m > 1 are denoted as ‘early clonal’ (co-amplified). In cases with f  = 1, m  = 1 and C > 2, mutations were annotated as ‘late clonal’, if the minor copy number was 0, otherwise ‘clonal’ (unspecified).

Timing of driver mutations

A catalogue of driver point mutations (SNVs and indels) was provided by the PCAWG Drivers and Functional Interpretation Group 4 . The timing category was calculated as above. From the four timing categories, the odds ratios of early/late clonal and clonal (early, late or unspecified clonal)/subclonal were calculated for driver mutations against the distribution of all other mutations present in fragments with the same copy number composition in the samples with each particular driver. The background distribution of these odds ratios was assessed with 1,000 bootstraps ( Supplementary Information, section 4.1 ).

Integrative timing

For each pair of driver point mutations and recurrent copy number alterations, an ordering was established (earlier, later or unspecified). The information underlying this decision was derived from the timing of each driver point mutation, as well as from the timing status of clonal and subclonal copy number segments. These tables were aggregated across all samples and a sports statistics model was employed to calculate the overall ranking of driver mutations. A full description is given in  Supplementary Information, section 4.2 .

Mutational trinucleotide substitution signatures, as defined by the PCAWG Mutational Signatures Working Group 24 , were fit to samples with observed signature activity, after splitting point mutations into either of the four epochs. A likelihood ratio test based on the multinomial distribution was used to test for differences in the mutation spectra between time points. Time-resolved exposures were calculated using non-negative linear least squares. Full details are given in Supplementary Information, section 5 .

Real-time estimation of WGD and MRCA

CpG>TpG mutations were counted in an NpCpG context, except for skin–melanoma, in which CpCpG and TpCpG were excluded owing to the overlapping UV mutation spectrum. For visual comparison, the number of mutations was scaled to the effective genome size, defined as the 1/mean( m i / C i ), in which m i is the estimated number of allelic copies of each mutation, and C i is the total copy number at that locus, thereby scaling to the final copy number and the time of change.

A hierarchical Bayesian linear regression was fit to relate the age at diagnosis to the scaled number of mutations, ensuring positive slope and intercept through a shared gamma distribution across cancer types.

For tumours with several time points, the set of mutations shared between diagnosis and relapse ( n D ) and those specific to the relapse ( n R ) was calculated. The rate acceleration was calculated as: a  =  n R / n D  ×  t D / t R . This analysis was performed separately for all substitutions and for CpG>TpG mutations.

On the basis of these analyses, a typical increase of 5× for most cancer types was chosen, with a lower value of 2.5× for brain cancers and a value of 7.5× for ovarian cancer.

The correction for transforming an estimate of a copy number gain in mutation time into chronological time depends not only on the rate acceleration, but also on the time at which this acceleration occurred. As this is generally unknown, we performed Monte Carlo simulations of rate accelerations spanning an interval of 15 years before diagnosis, corresponding roughly to 25% of time for a diagnosis at 60 years of age, noting that a 5× rate increase over this duration yields an offset of about 33% of mutations, compatible with our data. Subclonal mutations were assumed to occur at full acceleration. The proportion of subclonal mutations was divided by the number of identified subclones, thus conservatively assuming branching evolution. Full details are given in  Supplementary Information, section 6 .

Cancer timelines

The results from each of the different timing analyses are combined in timelines of cancer evolution for each tumour type (Fig. 6 and Supplementary Information ). Each timeline begins at the fertilized egg, and spans up to the median age of diagnosis within each cohort. Real-time estimates for WGD and the MRCA act as anchor points, allowing us to roughly map the four broadly defined time periods (early clonal, intermediate, late clonal and subclonal) to chronological time during a patient’s lifespan. Specific driver mutations or copy number alterations can be placed within each of these time frames based on their ordering from the league model analysis. Signatures are shown if they typically change over time (95% confidence intervals of mean change not overlapping 0), and if they are strongly active (contributing at least 10% mutations to one time point). Signatures are shown on the timeline in the epoch of their greatest activity. Where an event found in our study has a known timing in the literature, the agreement is annotated on the timeline; with an asterisk denoting an agreed timing, and dagger symbol denoting a timing that is different to our results. Full details are given in  Supplementary Information, section 7 .

Reporting summary

Further information on research design is available in the  Nature Research Reporting Summary linked to this paper.

Data availability

Somatic and germline variant calls, mutational signatures, subclonal reconstructions, transcript abundance, splice calls and other core data generated by the ICGC/TCGA PCAWG Consortium are described elsewhere 4 and available for download at https://dcc.icgc.org/releases/PCAWG . Further information on accessing the data, including raw read files, can be found at https://docs.icgc.org/pcawg/data/ . In accordance with the data access policies of the ICGC and TCGA projects, most molecular, clinical and specimen data are in an open tier that does not require access approval. To access information that could potentially identify participants, such as germline alleles and underlying sequencing data, researchers will need to apply to the TCGA Data Access Committee (DAC) via dbGaP ( https://dbgap.ncbi.nlm.nih.gov/aa/wga.cgi?page=login ) for access to the TCGA portion of the dataset, and to the ICGC Data Access Compliance Office (DACO; http://icgc.org/daco ) for the ICGC portion. In addition, to access somatic SNVs derived from TCGA donors, researchers will also need to obtain dbGaP authorization. Datasets used and results presented in this study, including timing estimates for copy number gains, chronological estimates of WGD and MRCA, as well as mutation signature changes, are described in  Supplementary Note 3 and are available at https://dcc.icgc.org/releases/PCAWG/evolution-heterogeneity .

Code availability

The core computational pipelines used by the PCAWG Consortium for alignment, quality control and variant calling are available to the public at https://dockstore.org/search?search=pcawg under the GNU General Public License v3.0, which allows for reuse and distribution. Analysis code presented in this study is available through the GitHub repository https://github.com/PCAWG-11/Evolution . This archive contains relevant software and analysis workflows as submodules, which include code for timing copy number gains, point mutations and mutation signatures, real-time timing and evolutionary league model analysis, as well as scripts to generate the figures presented: CancerTiming (v.3.1.8), MutationTimeR (v.0.1), PhylogicNDT (v.1.1) and a series of custom scripts (v. 1.0), with detailed versions of other packages used.

Change history

25 january 2023.

A Correction to this paper has been published: https://doi.org/10.1038/s41586-022-05601-4

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Acknowledgements

We thank H. Lee-Six and L. Moore for sharing data on mutation burden in normal tissues. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202) and the Wellcome Trust (FC001202). This project was enabled through the Crick Scientific Computing STP and through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council (grant number MR/L016311/1). M.T. and J.D. are postdoctoral fellows supported by the European Union’s Horizon 2020 research and innovation program (Marie Skłodowska-Curie grant agreement number 747852-SIOMICS and 703594-DECODE). J.D. is a postdoctoral fellow of the FWO. F.M., G.M. and K. Yuan acknowledge the support of the University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited. G.M., K. Yuan and F.M. were funded by CRUK core grants C14303/A17197 and A19274. S. Sengupta and Y.J. are supported by NIH R01 CA132897. S.M. is supported by the Vanier Canada Graduate Scholarship. S.C.S. is supported by the NSERC Discovery Frontiers Project, “The Cancer Genome Collaboratory” and NIH Grant GM108308. H.Z. is supported by grant NIMH086633 and an endowed Bao-Shan Jing Professorship in Diagnostic Imaging. W.W. is supported by the US National Cancer Institute (1R01 CA183793 and P30 CA016672). P.T.S. was supported by U24CA210957 and 1U24CA143799. D.C.W. is funded by the Li Ka Shing foundation. P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation’s support towards the establishment of The Francis Crick Institute. We acknowledge the contributions of the many clinical networks across ICGC and TCGA who provided samples and data to the PCAWG Consortium, and the contributions of the Technical Working Group and the Germline Working Group of the PCAWG Consortium for collation, realignment and harmonized variant calling of the cancer genomes used in this study. We thank the patients and their families for their participation in the individual ICGC and TCGA projects.

Author information

These authors contributed equally: Moritz Gerstung, Clemency Jolly, Ignaty Leshchiner, Stefan C. Dentro, Santiago Gonzalez

These authors jointly supervised this work: Paul T. Spellman, David C. Wedge, Peter Van Loo

A list of members and their affiliations appears at the end of the paper

A list of members and their affiliations appears online

Authors and Affiliations

European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Cambridge, UK

Moritz Gerstung, Santiago Gonzalez, Lara Jerman, Moritz Gerstung, Santiago Gonzalez & Lara Jerman

European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany

Moritz Gerstung & Moritz Gerstung

Wellcome Sanger Institute, Cambridge, UK

Moritz Gerstung, Stefan C. Dentro, Thomas J. Mitchell, Maxime Tarabichi, Ignacio Vázquez-García, Stefan C. Dentro, Moritz Gerstung, Maxime Tarabichi, David J. Adams, Peter J. Campbell, Kevin J. Dawson, Henry Lee-Six, Inigo Martincorena, Thomas J. Mitchell & Ignacio Vázquez-García

The Francis Crick Institute, London, UK

Clemency Jolly, Stefan C. Dentro, Maxime Tarabichi, Kerstin Haase, Jonas Demeulemeester, Stefan C. Dentro, Clemency Jolly, Kerstin Haase, Maxime Tarabichi, Jonas Demeulemeester, Matthew Fittall, Peter Van Loo & Peter Van Loo

Broad Institute of MIT and Harvard, Cambridge, MA, USA

Ignaty Leshchiner, Daniel Rosebrock, Dimitri G. Livitz, Steven Schumacher, Gad Getz, Rameen Beroukhim, Ignaty Leshchiner, Rameen Beroukhim, Gad Getz, Gavin Ha, Dimitri G. Livitz, Daniel Rosebrock, Steven Schumacher & Oliver Spiro

Big Data Institute, University of Oxford, Oxford, UK

Stefan C. Dentro, Stefan C. Dentro, David C. Wedge & David C. Wedge

University of Cambridge, Cambridge, UK

Thomas J. Mitchell, Ignacio Vázquez-García, Thomas J. Mitchell & Ignacio Vázquez-García

University of Toronto, Toronto, Ontario, Canada

Yulia Rubanova, Amit Deshwar, Jeff Wintersinger, Paul C. Boutros, Quaid D. Morris, Jeff Wintersinger, Amit G. Deshwar, Yulia Rubanova, Paul C. Boutros, Ruian Shi, Shankar Vembu & Quaid D. Morris

Vector Institute, Toronto, Ontario, Canada

Yulia Rubanova, Amit Deshwar, Jeff Wintersinger, Quaid D. Morris, Jeff Wintersinger, Amit G. Deshwar, Yulia Rubanova & Quaid D. Morris

Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA

Pavana Anur, Pavana Anur, Myron Peto, Paul T. Spellman & Paul T. Spellman

The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Kaixian Yu, Yu Fan, Hongtu Zhu, Wenyi Wang, Kaixian Yu, Shaolong Cao, Yu Fan, Seung Jun Shin, Hongtu Zhu & Wenyi Wang

German Cancer Research Center (DKFZ), Heidelberg, Germany

Kortine Kleinheinz, Matthias Schlesner, Roland Eils, Kortine Kleinheinz & Matthias Schlesner

Heidelberg University, Heidelberg, Germany

Kortine Kleinheinz, Roland Eils & Kortine Kleinheinz

University of Ljubljana, Ljubljana, Slovenia

Lara Jerman & Lara Jerman

NorthShore University HealthSystem, Evanston, IL, USA

Subhajit Sengupta, Yuan Ji, Yuan Ji & Subhajit Sengupta

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK

Geoff Macintyre, Florian Markowetz, Ke Yuan, Geoff Macintyre, Ruben M. Drews, Florian Markowetz & Ke Yuan

Simon Fraser University, Burnaby, British Columbia, Canada

Salem Malikic, Nilgun Donmez, Nilgun Donmez & Salem Malikic

Vancouver Prostate Centre, Vancouver, British Columbia, Canada

Salem Malikic, Nilgun Donmez, S. Cenk Sahinalp, Nilgun Donmez, Salem Malikic & S. Cenk Sahinalp

University of Melbourne, Melbourne, Victoria, Australia

Marek Cmero, Elizabeth L. Christie, Marek Cmero & Dale W. Garsed

Walter and Eliza Hall Institute, Melbourne, Victoria, Australia

Marek Cmero & Marek Cmero

University of Leuven, Leuven, Belgium

Jonas Demeulemeester, Jonas Demeulemeester, Peter Van Loo & Peter Van Loo

Weill Cornell Medicine, New York, NY, USA

Xiaotong Yao, Marcin Imielinski, Marcin Imielinski & Xiaotong Yao

New York Genome Center, New York, NY, USA

University of California Santa Cruz, Santa Cruz, CA, USA

Juhee Lee & Juhee Lee

Ontario Institute for Cancer Research, Toronto, Ontario, Canada

Paul C. Boutros, Paul C. Boutros, Adriana Salcedo & Lincoln D. Stein

University of California, Los Angeles, CA, USA

Paul C. Boutros & Paul C. Boutros

Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

David D. Bowtell, David D. Bowtell, Elizabeth L. Christie & Dale W. Garsed

Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA

Gad Getz & Gad Getz

Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

Harvard Medical School, Boston, MA, USA

Dana-Farber Cancer Institute, Boston, MA, USA

Rameen Beroukhim & Rameen Beroukhim

Indiana University, Bloomington, IN, USA

S. Cenk Sahinalp & S. Cenk Sahinalp

The University of Chicago, Chicago, IL, USA

Yuan Ji & Yuan Ji

University of Cologne, Cologne, Germany

Martin Peifer, Yupeng Cun, Martin Peifer & Tsun-Po Yang

University of Helsinki, Helsinki, Finland

Ville Mustonen & Ville Mustonen

University of Glasgow, Glasgow, UK

Ke Yuan & Ke Yuan

Oxford NIHR Biomedical Research Centre, Oxford, UK

David C. Wedge & David C. Wedge

Department of Computer Science, Carleton College, Northfield, MN, USA

Layla Oesper

Department of Computer Science, Princeton University, Princeton, NJ, USA

Benjamin J. Raphael

Korea University, Seoul, South Korea

Seung Jun Shin

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA

David A. Wheeler

Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland

• Lauri A. Aaltonen

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK

Federico Abascal, David J. Adams, Ludmil B. Alexandrov, Sam Behjati, Shriram G. Bhosle, David T. Bowen, Adam P. Butler, Peter J. Campbell, Peter Clapham, Helen Davies, Kevin J. Dawson, Stefan C. Dentro, Serge Serge, Erik Garrison, Mohammed Ghori, Dominik Glodzik, Jonathan Hinton, David R. Jones, Young Seok Ju, Stian Knappskog, Barbara Kremeyer, Henry Lee-Six, Daniel A. Leongamornlert, Yilong Li, Sancha Martin, Iñigo Martincorena, Ultan McDermott, Andrew Menzies, Thomas J. Mitchell, Sandro Morganella, Jyoti Nangalia, Jonathan Nicholson, Serena Nik-Zainal, Sarah O’Meara, Elli Papaemmanuil, Keiran M. Raine, Manasa Ramakrishna, Kamna Ramakrishnan, Nicola D. Roberts, Rebecca Shepherd, Lucy Stebbings, Michael R. Stratton, Maxime Tarabichi, Jon W. Teague, Ignacio Vázquez-García, David C. Wedge, Lucy Yates, Jorge Zamora & Xueqing Zou

Memorial Sloan Kettering Cancer Center, New York, NY, USA

Adam Abeshouse, Hikmat Al-Ahmadie, Gunes Gundem, Zachary Heins, Jason Huse, Douglas A. Levine, Eric Minwei Liu & Angelica Ochoa

Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan

Hiroyuki Aburatani, Genta Nagae, Akihiro Suzuki, Kenji Tatsuno & Shogo Yamamoto

Department of Surgery, University of Chicago, Chicago, IL, USA

Nishant Agrawal

Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, School of Medicine, Keimyung University Dongsan Medical Center, Daegu, South Korea

Keun Soo Ahn & Koo Jeong Kang

Department of Oncology, Gil Medical Center, Gachon University, Incheon, South Korea

Sung-Min Ahn

Hiroshima University, Hiroshima, Japan

Hiroshi Aikata, Koji Arihiro, Kazuaki Chayama, Yoshiiku Kawakami & Hideki Ohdan

Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Rehan Akbani, Shaolong Cao, Yiwen Chen, Zechen Chong, Yu Fan, Jun Li, Han Liang, Wenyi Wang, Yumeng Wang & Yuan Yuan

University of Texas MD Anderson Cancer Center, Houston, TX, USA

Kadir C. Akdemir & Ken Chen

King Faisal Specialist Hospital and Research Centre, Al Maather, Riyadh, Saudi Arabia

Sultan T. Al-Sedairy

Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

Fatima Al-Shahrour & Elena Piñeiro-Yáñez

Bioinformatics Core Facility, University Medical Center Hamburg, Hamburg, Germany

Malik Alawi

Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany

Malik Alawi & Adam Grundhoff

Ontario Tumour Bank, Ontario Institute for Cancer Research, Toronto, ON, Canada

Monique Albert & John Bartlett

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Kenneth Aldape, Russell R. Broaddus, Bogdan Czerniak, Adel El-Naggar, Savitri Krishnamurthy, Alexander J. Lazar & Xiaoping Su

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

Kenneth Aldape

Department of Cellular and Molecular Medicine and Department of Bioengineering, University of California San Diego, La Jolla, CA, USA

Ludmil B. Alexandrov & Erik N. Bergstrom

UC San Diego Moores Cancer Center, San Diego, CA, USA

Ludmil B. Alexandrov, Erik N. Bergstrom & Olivier Harismendy

Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada

Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert A. Holt, Steven J. M. Jones, Katayoon Kasaian, Darlene Lee, Haiyan Irene Li, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen & Tina Wong

Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia

Kathryn Alsop, David D. L. Bowtell, Elizabeth L. Christie, Dariush Etemadmoghadam, Sian Fereday, Dale W. Garsed, Linda Mileshkin, Chris Mitchell, Mark Shackleton, Heather Thorne & Nadia Traficante

Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain

Eva G. Alvarez, Alicia L. Bruzos, Bernardo Rodriguez-Martin, Javier Temes, Jose M. C. Tubio & Jorge Zamora

Department of Zoology, Genetics and Physical Anthropology, (CiMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain

The Biomedical Research Centre (CINBIO), Universidade de Vigo, Vigo, Spain

Eva G. Alvarez, Alicia L. Bruzos, Bernardo Rodriguez-Martin, Marta Tojo, Jose M. C. Tubio & Jorge Zamora

Royal National Orthopaedic Hospital - Bolsover, London, UK

Fernanda Amary

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Samirkumar B. Amin, P. Andrew Futreal & Alexander J. Lazar

Quantitative and Computational Biosciences Graduate Program, Baylor College of Medicine, Houston, TX, USA

Samirkumar B. Amin, Han Liang & Yumeng Wang

The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA

Samirkumar B. Amin, Joshy George & Lucas Lochovsky

Genome Informatics Program, Ontario Institute for Cancer Research, Toronto, ON, Canada

Brice Aminou, Niall J. Byrne, Aurélien Chateigner, Nodirjon Fayzullaev, Vincent Ferretti, George L. Mihaiescu, Hardeep K. Nahal-Bose, Brian D. O’Connor, B. F. Francis Ouellette, Marc D. Perry, Kevin Thai, Qian Xiang, Christina K. Yung & Junjun Zhang

Institute of Human Genetics, Christian-Albrechts-University, Kiel, Germany

Ole Ammerpohl, Andrea Haake, Cristina López, Julia Richter & Rabea Wagener

Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany

Ole Ammerpohl, Sietse Aukema, Cristina López, Reiner Siebert & Rabea Wagener

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Brisbane, QLD, Australia

Matthew J. Anderson, Timothy J. C. Bruxner, Angelika N. Christ, J. Lynn Fink, Ivon Harliwong, Karin S. Kassahn, David K. Miller, Alan J. Robertson & Darrin F. Taylor

Salford Royal NHS Foundation Trust, Salford, UK

Yeng Ang, Hsiao-Wei Chen, Ritika Kundra & Francisco Sanchez-Vega

Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy

Davide Antonello, Claudio Bassi, Narong Khuntikeo, Luca Landoni, Giuseppe Malleo, Giovanni Marchegiani, Neil D. Merrett, Marco Miotto, Salvatore Paiella, Antonio Pea, Paolo Pederzoli, Roberto Salvia, Jaswinder S. Samra, Elisabetta Sereni & Samuel Singer

Molecular and Medical Genetics, OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA

Pavana Anur, Myron Peto & Paul T. Spellman

Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada

Samuel Aparicio

The McDonnell Genome Institute at Washington University, St. Louis, MO, USA

Elizabeth L. Appelbaum, Matthew H. Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Kuan-lin Huang, Reyka Jayasinghe, Elaine R. Mardis, R. Jay Mashl, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Jiayin Wang, Michael C. Wendl, Richard K. Wilson & Tina Wong

University College London, London, UK

Elizabeth L. Appelbaum, Jonathan D. Kay, Helena Kilpinen, Laurence B. Lovat, Hayley J. Luxton & Hayley C. Whitaker

Division of Cancer Genomics, National Cancer Center Research Institute, National Cancer Center, Tokyo, Japan

Yasuhito Arai, Natsuko Hama, Fumie Hosoda, Hiromi Nakamura, Tatsuhiro Shibata, Yasushi Totoki & Shinichi Yachida

DLR Project Management Agency, Bonn, Germany

Tokyo Women’s Medical University, Tokyo, Japan

Shun-ichi Ariizumi & Masakazu Yamamoto

Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Joshua Armenia, Hsiao-Wei Chen, Jianjiong Gao, Ritika Kundra, Francisco Sanchez-Vega, Nikolaus Schultz & Hongxin Zhang

Los Alamos National Laboratory, Los Alamos, NM, USA

Laurent Arnould

Department of Pathology, University Health Network, Toronto General Hospital, Toronto, ON, Canada

Sylvia Asa, Michael H. A. Roehrl & Theodorus Van der Kwast

Nottingham University Hospitals NHS Trust, Nottingham, UK

Sylvia Asa, Simon L. Parsons & Ming Tsao

Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany

Yassen Assenov

Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada

Gurnit Atwal, Philip Awadalla, Jonathan Barenboim, Vinayak Bhandari, Ivan Borozan, Paul C. Boutros, Lewis Jonathan Dursi, Shadrielle M. G. Espiritu, Natalie S. Fox, Michael Fraser, Syed Haider, Vincent Huang, Keren Isaev, Wei Jiao, Christopher M. Lalansingh, Emilie Lalonde, Fabien C. Lamaze, Constance H. Li, Julie Livingstone, Christine P’ng, Marta Paczkowska, Stephenie D. Prokopec, Jüri Reimand, Veronica Y. Sabelnykova, Adriana Salcedo, Yu-Jia Shiah, Solomon I. Shorser, Shimin Shuai, Jared T. Simpson, Lincoln D. Stein, Ren X. Sun, Lina Wadi, Gavin W. Wilson, Adam J. Wright, Takafumi N. Yamaguchi, Fouad Yousif & Denis Yuen

Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

Gurnit Atwal, Philip Awadalla, Gary D. Bader, Shimin Shuai & Lincoln D. Stein

Vector Institute, Toronto, ON, Canada

Gurnit Atwal, Quaid D. Morris, Yulia Rubanova & Jeffrey A. Wintersinger

Hematopathology Section, Institute of Pathology, Christian-Albrechts-University, Kiel, Germany

Sietse Aukema, Wolfram Klapper, Julia Richter & Monika Szczepanowski

Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

J. Todd Auman & Charles M. Perou

Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway

Miriam R. R. Aure, Anne-Lise Børresen-Dale & Anita Langerød

Pathology, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain

Marta Aymerich

Department of Veterinary Medicine, Transmissible Cancer Group, University of Cambridge, Cambridge, UK

Adrian Baez-Ortega

Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA

Matthew H. Bailey, Li Ding, Robert S. Fulton, Ramaswamy Govindan & Michael D. McLellan

Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK

Peter J. Bailey, Andrew V. Biankin, David K. Chang, Susanna L. Cooke, Fraser R. Duthie, Janet S. Graham, Nigel B. Jamieson, Elizabeth A. Musgrove & Derek W. Wright

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Saianand Balu, Tom Bodenheimer, D. Neil Hayes, Austin J. Hepperla, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Shaowu Meng, Lisle E. Mose, Grant Sanders, Yan Shi, Janae V. Simons & Matthew G. Soloway

Pratiti Bandopadhayay, Rameen Beroukhim, Angela N. Brooks, Susan Bullman, John Busanovich, Andrew D. Cherniack, Juok Cho, Carrie Cibulskis, Kristian Cibulskis, David Craft, Timothy Defreitas, Andrew J. Dunford, Scott Frazer, Stacey B. Gabriel, Nils Gehlenborg, Gad Getz, Manaswi Gupta, Gavin Ha, Nicholas J. Haradhvala, David I. Heiman, Julian M. Hess, Manolis Kellis, Jaegil Kim, Kiran Kumar, Kirsten Kübler, Eric Lander, Michael S. Lawrence, Ignaty Leshchiner, Pei Lin, Ziao Lin, Dimitri Livitz, Yosef E. Maruvka, Samuel R. Meier, Matthew Meyerson, Michael S. Noble, Chandra Sekhar Pedamallu, Paz Polak, Esther Rheinbay, Daniel Rosebrock, Mara Rosenberg, Gordon Saksena, Richard Sallari, Steven E. Schumacher, Ayellet V. Segre, Ofer Shapira, Juliann Shih, Nasa Sinnott-Armstrong, Oliver Spiro, Chip Stewart, Amaro Taylor-Weiner, Grace Tiao, Douglas Voet, Jeremiah A. Wala, Cheng-Zhong Zhang & Hailei Zhang

Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA

Pratiti Bandopadhayay

Department of Pediatrics, Harvard Medical School, Boston, MA, USA

Leeds Institute of Medical Research @ St. James’s, University of Leeds, St. James’s University Hospital, Leeds, UK

Rosamonde E. Banks & Naveen Vasudev

Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy

Stefano Barbi, Vincenzo Corbo & Michele Simbolo

Department of Surgery, Princess Alexandra Hospital, Brisbane, QLD, Australia

Andrew P. Barbour

Surgical Oncology Group, Diamantina Institute, University of Queensland, Brisbane, QLD, Australia

Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA

Jill Barnholtz-Sloan

Research Health Analytics and Informatics, University Hospitals Cleveland Medical Center, Cleveland, OH, USA

Gloucester Royal Hospital, Gloucester, UK

Elisabet Barrera, Wojciech Bazant, Ewan Birney, Rich Boyce, Alvis Brazma, Andy Cafferkey, Claudia Calabrese, Paul Flicek, Nuno A. Fonseca, Anja Füllgrabe, Moritz Gerstung, Santiago Gonzalez, Liliana Greger, Maria Keays, Jan O. Korbel, Alfonso Muñoz, Steven J. Newhouse, David Ocana, Irene Papatheodorou, Robert Petryszak, Roland F. Schwarz, Charles Short, Oliver Stegle & Lara Urban

Diagnostic Development, Ontario Institute for Cancer Research, Toronto, ON, Canada

John Bartlett & Ilinca Lungu

Barcelona Supercomputing Center (BSC), Barcelona, Spain

Javier Bartolome, Mattia Bosio, Ana Dueso-Barroso, J. Lynn Fink, Josep L. L. Gelpi, Ana Milovanovic, Montserrat Puiggròs, Javier Bartolomé Rodriguez, Romina Royo, David Torrents, Alfonso Valencia, Miguel Vazquez, David Vicente & Izar Villasante

Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada

Oliver F. Bathe

Departments of Surgery and Oncology, University of Calgary, Calgary, AB, Canada

Department of Pathology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway

Daniel Baumhoer & Bodil Bjerkehagen

PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada

Prashant Bavi, Michelle Chan-Seng-Yue, Sean Cleary, Robert E. Denroche, Steven Gallinger, Robert C. Grant, Gun Ho Jang, Sangeetha Kalimuthu, Ilinca Lungu, John D. McPherson, Faiyaz Notta, Michael H. A. Roehrl, Gavin W. Wilson & Julie M. Wilson

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine, Baltimore, MD, USA

Stephen B. Baylin, Nilanjan Chatterjee, Leslie Cope, Ludmila Danilova & Ralph H. Hruban

University Hospital Southampton NHS Foundation Trust, Southampton, UK

Stephen B. Baylin & Tim Dudderidge

Royal Stoke University Hospital, Stoke-on-Trent, UK

Duncan Beardsmore & Christopher Umbricht

Genome Sequence Informatics, Ontario Institute for Cancer Research, Toronto, ON, Canada

Timothy A. Beck, Bob Gibson, Lawrence E. Heisler, Xuemei Luo & Morgan L. Taschuk

Human Longevity Inc, San Diego, CA, USA

Timothy A. Beck

Olivia Newton-John Cancer Research Institute, La Trobe University, Heidelberg, VIC, Australia

Andreas Behren & Jonathan Cebon

Computer Network Information Center, Chinese Academy of Sciences, Beijing, China

Beifang Niu

Genome Canada, Ottawa, ON, Canada

CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain

Sergi Beltran, Ivo G. Gut, Marta Gut, Simon C. Heath, Tomas Marques-Bonet, Arcadi Navarro, Miranda D. Stobbe, Jean-Rémi Trotta & Justin P. Whalley

Universitat Pompeu Fabra (UPF), Barcelona, Spain

Sergi Beltran, Mattia Bosio, German M. Demidov, Oliver Drechsel, Ivo G. Gut, Marta Gut, Simon C. Heath, Francesc Muyas, Stephan Ossowski, Aparna Prasad, Raquel Rabionet, Miranda D. Stobbe & Hana Susak

Buck Institute for Research on Aging, Novato, CA, USA

Christopher Benz & Christina Yau

Duke University Medical Center, Durham, NC, USA

Andrew Berchuck

Department of Human Genetics, Hannover Medical School, Hannover, Germany

Anke K. Bergmann

Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Benjamin P. Berman & Huy Q. Dinh

Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Benjamin P. Berman

The Hebrew University Faculty of Medicine, Jerusalem, Israel

Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

Daniel M. Berney & Yong-Jie Lu

Department of Computer Science, Bioinformatics Group, University of Leipzig, Leipzig, Germany

Stephan H. Bernhart, Hans Binder, Steve Hoffmann & Peter F. Stadler

Interdisciplinary Center for Bioinformatics, University of Leipzig, Leipzig, Germany

Stephan H. Bernhart, Hans Binder, Steve Hoffmann, Helene Kretzmer & Peter F. Stadler

Transcriptome Bioinformatics, LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany

Stephan H. Bernhart, Steve Hoffmann, Helene Kretzmer & Peter F. Stadler

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

Rameen Beroukhim, Angela N. Brooks, Susan Bullman, Andrew D. Cherniack, Levi Garraway, Matthew Meyerson, Chandra Sekhar Pedamallu, Steven E. Schumacher, Juliann Shih & Jeremiah A. Wala

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

Rameen Beroukhim, Aquila Fatima, Andrea L. Richardson, Steven E. Schumacher, Ofer Shapira, Andrew Tutt & Jeremiah A. Wala

Rameen Beroukhim, Gad Getz, Kirsten Kübler, Matthew Meyerson, Chandra Sekhar Pedamallu, Paz Polak, Esther Rheinbay & Jeremiah A. Wala

USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

Mario Berrios, Moiz S. Bootwalla, Andrea Holbrook, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg & Daniel J. Weisenberger

Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy

Samantha Bersani, Ivana Cataldo, Claudio Luchini & Maria Scardoni

Department of Mathematics, Aarhus University, Aarhus, Denmark

Johanna Bertl & Asger Hobolth

Department of Molecular Medicine (MOMA), Aarhus University Hospital, Aarhus N, Denmark

Johanna Bertl, Henrik Hornshøj, Malene Juul, Randi Istrup Juul, Tobias Madsen, Morten Muhlig Nielsen & Jakob Skou Pedersen

Instituto Carlos Slim de la Salud, Mexico City, Mexico

Miguel Betancourt

Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

Vinayak Bhandari, Paul C. Boutros, Robert G. Bristow, Keren Isaev, Constance H. Li, Jüri Reimand, Michael H. A. Roehrl & Bradly G. Wouters

Cancer Division, Garvan Institute of Medical Research, Kinghorn Cancer Centre, University of New South Wales (UNSW Sydney), Sydney, NSW, Australia

Andrew V. Biankin, David K. Chang, Lorraine A. Chantrill, Angela Chou, Anthony J. Gill, Amber L. Johns, James G. Kench, David K. Miller, Adnan M. Nagrial, Marina Pajic, Mark Pinese, Ilse Rooman, Christopher J. Scarlett, Christopher W. Toon & Jianmin Wu

South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales (UNSW Sydney), Liverpool, NSW, Australia

Andrew V. Biankin

West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK

Andrew V. Biankin & Nigel B. Jamieson

Center for Digital Health, Berlin Institute of Health and Charitè - Universitätsmedizin Berlin, Berlin, Germany

Matthias Bieg

Heidelberg Center for Personalized Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), Heidelberg, Germany

Matthias Bieg, Ivo Buchhalter, Barbara Hutter & Nagarajan Paramasivam

The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA

Darell Bigner

Massachusetts General Hospital, Boston, MA, USA

Michael Birrer, Vikram Deshpande, William C. Faquin, Nicholas J. Haradhvala, Kirsten Kübler, Michael S. Lawrence, David N. Louis, Yosef E. Maruvka, G. Petur Nielsen, Esther Rheinbay, Mara Rosenberg, Dennis C. Sgroi & Chin-Lee Wu

National Institute of Biomedical Genomics, Kalyani, West Bengal, India

Nidhan K. Biswas, Arindam Maitra & Partha P. Majumder

Institute of Clinical Medicine and Institute of Oral Biology, University of Oslo, Oslo, Norway

Bodil Bjerkehagen

University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Lori Boice, Mei Huang, Sonia Puig & Leigh B. Thorne

ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy

Giada Bonizzato, Cinzia Cantù, Ivana Cataldo, Vincenzo Corbo, Sonia Grimaldi, Rita T. Lawlor, Andrea Mafficini, Borislav C. Rusev, Aldo Scarpa, Katarzyna O. Sikora, Nicola Sperandio, Alain Viari & Caterina Vicentini

The Institute of Cancer Research, London, UK

Johann S. De Bono, Niedzica Camacho, Colin S. Cooper, Sandra E. Edwards, Rosalind A. Eeles, Zsofia Kote-Jarai, Daniel A. Leongamornlert, Lucy Matthews & Sue Merson

Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore

Arnoud Boot, Ioana Cutcutache, Mi Ni Huang, John R. McPherson, Steven G. Rozen & Yang Wu

Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore

Arnoud Boot, Ioana Cutcutache, Mi Ni Huang, John R. McPherson, Steven G. Rozen, Patrick Tan, Bin Tean Teh & Yang Wu

Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden

Ake Borg, Markus Ringnér & Johan Staaf

Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany

Arndt Borkhardt & Jessica I. Hoell

Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

Keith A. Boroevich, Todd A. Johnson, Michael S. Lawrence & Tatsuhiko Tsunoda

RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

Keith A. Boroevich, Akihiro Fujimoto, Masashi Fujita, Mayuko Furuta, Kazuhiro Maejima, Hidewaki Nakagawa, Kaoru Nakano & Aya Sasaki-Oku

Department of Internal Medicine/Hematology, Friedrich-Ebert-Hospital, Neumünster, Germany

Christoph Borst & Siegfried Haas

Departments of Dermatology and Pathology, Yale University, New Haven, CT, USA

Marcus Bosenberg

Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain

Mattia Bosio, German M. Demidov, Oliver Drechsel, Georgia Escaramis, Xavier Estivill, Aliaksei Z. Holik, Francesc Muyas, Stephan Ossowski, Raquel Rabionet & Hana Susak

Radcliffe Department of Medicine, University of Oxford, Oxford, UK

Jacqueline Boultwood

Canadian Center for Computational Genomics, McGill University, Montreal, QC, Canada

Guillaume Bourque

Department of Human Genetics, McGill University, Montreal, QC, Canada

Guillaume Bourque, Mark Lathrop & Yasser Riazalhosseini

Department of Human Genetics, University of California Los Angeles, Los Angeles, CA, USA

Paul C. Boutros

Department of Pharmacology, University of Toronto, Toronto, ON, Canada

Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Tampere, Finland

G. Steven Bova & Tapio Visakorpi

Haematology, Leeds Teaching Hospitals NHS Trust, Leeds, UK

David T. Bowen

Translational Research and Innovation, Centre Léon Bérard, Lyon, France

Sandrine Boyault

Fox Chase Cancer Center, Philadelphia, PA, USA

Jeffrey Boyd & Elaine R. Mardis

International Agency for Research on Cancer, World Health Organization, Lyon, France

Paul Brennan & Ghislaine Scelo

Earlham Institute, Norwich, UK

Daniel S. Brewer & Colin S. Cooper

Norwich Medical School, University of East Anglia, Norwich, UK

Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, HB, The Netherlands

Arie B. Brinkman

CRUK Manchester Institute and Centre, Manchester, UK

Robert G. Bristow

Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada

Division of Cancer Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester, UK

Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON, Canada

Robert G. Bristow & Fei-Fei Fei Liu

Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

Jane E. Brock & Sabina Signoretti

Department of Surgery, Division of Thoracic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

Malcolm Brock

Division of Molecular Pathology, The Netherlands Cancer Institute, Oncode Institute, Amsterdam, CX, The Netherlands

Annegien Broeks & Jos Jonkers

Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, USA

Angela N. Brooks, David Haan, Maximillian G. Marin, Thomas J. Matthew, Yulia Newton, Cameron M. Soulette & Joshua M. Stuart

UC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA, USA

Angela N. Brooks, Brian Craft, Mary J. Goldman, David Haussler, Joshua M. Stuart & Jingchun Zhu

Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Benedikt Brors, Lars Feuerbach, Chen Hong, Charles David Imbusch & Lina Sieverling

German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

Benedikt Brors, Barbara Hutter, Peter Lichter, Dirk Schadendorf & Holger Sültmann

National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany

Benedikt Brors, Barbara Hutter, Holger Sültmann & Thorsten Zenz

Center for Biological Sequence Analysis, Department of Bio and Health Informatics, Technical University of Denmark, Lyngby, Denmark

Søren Brunak

Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark

Institute for Molecular Bioscience, University of Queensland, St. Lucia, Brisbane, QLD, Australia

Timothy J. C. Bruxner, Oliver Holmes, Stephen H. Kazakoff, Conrad R. Leonard, Felicity Newell, Katia Nones, Ann-Marie Patch, John V. Pearson, Michael C. Quinn, Nick M. Waddell, Nicola Waddell, Scott Wood & Qinying Xu

Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA

Alex Buchanan & Kyle Ellrott

Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Ivo Buchhalter, Calvin Wing Yiu Chan, Roland Eils, Michael C. Heinold, Carl Herrmann, Natalie Jäger, Rolf Kabbe, Jules N. A. Kerssemakers, Kortine Kleinheinz, Nagarajan Paramasivam, Manuel Prinz, Matthias Schlesner & Johannes Werner

Institute of Pharmacy and Molecular Biotechnology and BioQuant, Heidelberg University, Heidelberg, Germany

Ivo Buchhalter, Roland Eils, Michael C. Heinold, Carl Herrmann, Daniel Hübschmann, Kortine Kleinheinz & Umut H. Toprak

Federal Ministry of Education and Research, Berlin, Germany

Christiane Buchholz

Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia

Hazel Burke, Ricardo De Paoli-Iseppi, Nicholas K. Hayward, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Georgina V. Long, Graham J. Mann, Robyn P. M. Saw, Richard A. Scolyer, Ping Shang, Andrew J. Spillane, Jonathan R. Stretch, John F. F. Thompson & James S. Wilmott

Pediatric Hematology and Oncology, University Hospital Muenster, Muenster, Germany

Birgit Burkhardt

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Kathleen H. Burns & Christopher Umbricht

McKusick-Nathans Institute of Genetic Medicine, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine, Baltimore, MD, USA

Kathleen H. Burns

Foundation Medicine, Inc, Cambridge, MA, USA

John Busanovich

Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA

Carlos D. Bustamante & Francisco M. De La Vega

Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA

Carlos D. Bustamante, Francisco M. De La Vega, Suyash S. Shringarpure, Nasa Sinnott-Armstrong & Mark H. Wright

Bakar Computational Health Sciences Institute and Department of Pediatrics, University of California, San Francisco, CA, USA

Atul J. Butte & Jieming Chen

Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway

Anne-Lise Børresen-Dale

National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen & Jiashan Zhang

Royal Marsden NHS Foundation Trust, London and Sutton, UK

Declan Cahill, Nening M. Dennis, Tim Dudderidge, Rosalind A. Eeles, Cyril Fisher, Steven Hazell, Vincent Khoo, Pardeep Kumar, Naomi Livni, Erik Mayer, David Nicol, Christopher Ogden, Edward W. Rowe, Sarah Thomas, Alan Thompson & Nicholas van As

Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany

Claudia Calabrese, Serap Erkek, Moritz Gerstung, Santiago Gonzalez, Nina Habermann, Wolfgang Huber, Lara Jerman, Jan O. Korbel, Esa Pitkänen, Benjamin Raeder, Tobias Rausch, Vasilisa A. Rudneva, Oliver Stegle, Stephanie Sungalee, Lara Urban, Sebastian M. Waszak, Joachim Weischenfeldt & Sergei Yakneen

Department of Oncology, University of Cambridge, Cambridge, UK

Carlos Caldas & Suet-Feung Chin

Li Ka Shing Centre, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK

Carlos Caldas, Suet-Feung Chin, Ruben M. Drews, Paul A. Edwards, Matthew Eldridge, Steve Hawkins, Andy G. Lynch, Geoff Macintyre, Florian Markowetz, Charlie E. Massie, David E. Neal, Simon Tavaré & Ke Yuan

Institut Gustave Roussy, Villejuif, France

Fabien Calvo

Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

Peter J. Campbell, Vincent J. Gnanapragasam, William Howat, Thomas J. Mitchell, David E. Neal, Nimish C. Shah & Anne Y. Warren

Department of Haematology, University of Cambridge, Cambridge, UK

Peter J. Campbell

Anatomia Patológica, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain

Elias Campo

Spanish Ministry of Science and Innovation, Madrid, Spain

University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA

Thomas E. Carey

Department for BioMedical Research, University of Bern, Bern, Switzerland

Joana Carlevaro-Fita

Department of Medical Oncology, Inselspital, University Hospital and University of Bern, Bern, Switzerland

Joana Carlevaro-Fita, Rory Johnson & Andrés Lanzós

Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland

Joana Carlevaro-Fita & Andrés Lanzós

University of Pavia, Pavia, Italy

Mario Cazzola & Luca Malcovati

University of Alabama at Birmingham, Birmingham, AL, USA

Robert Cerfolio

UHN Program in BioSpecimen Sciences, Toronto General Hospital, Toronto, ON, Canada

Dianne E. Chadwick, Sheng-Ben Liang, Michael H. A. Roehrl & Sagedeh Shahabi

Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Dimple Chakravarty

Centre for Law and Genetics, University of Tasmania, Sandy Bay Campus, Hobart, TAS, Australia

Don Chalmers

Faculty of Biosciences, Heidelberg University, Heidelberg, Germany

Calvin Wing Yiu Chan, Chen Hong & Lina Sieverling

Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada

Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA

Vishal S. Chandan

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Stephen J. Chanock, Xing Hua, Lisa Mirabello, Lei Song & Bin Zhu

Illawarra Shoalhaven Local Health District L3 Illawarra Cancer Care Centre, Wollongong Hospital, Wollongong, NSW, Australia

Lorraine A. Chantrill

BioForA, French National Institute for Agriculture, Food, and Environment (INRAE), ONF, Orléans, France

Aurélien Chateigner

Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

Nilanjan Chatterjee

University of California San Diego, San Diego, CA, USA

Zhaohong Chen, Michelle T. Dow, Claudiu Farcas, S. M. Ashiqul Islam, Antonios Koures, Lucila Ohno-Machado, Christos Sotiriou & Ashley Williams

Division of Experimental Pathology, Mayo Clinic, Rochester, MN, USA

Jeremy Chien

Centre for Cancer Research, The Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia

Yoke-Eng Chiew, Angela Chou, Jillian A. Hung, Catherine J. Kennedy, Graham J. Mann, Gulietta M. Pupo, Sarah-Jane Schramm, Varsha Tembe & Anna deFazio

Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia

Yoke-Eng Chiew, Jillian A. Hung, Catherine J. Kennedy & Anna deFazio

PDXen Biosystems Inc, Seoul, South Korea

Sunghoon Cho

Korea Advanced Institute of Science and Technology, Daejeon, South Korea

Jung Kyoon Choi, Young Seok Ju & Christopher J. Yoon

Electronics and Telecommunications Research Institute, Daejeon, South Korea

Wan Choi, Seung-Hyup Jeon, Hyunghwan Kim & Youngchoon Woo

Institut National du Cancer (INCA), Boulogne-Billancourt, France

Christine Chomienne & Iris Pauporté

Department of Genetics, Informatics Institute, University of Alabama at Birmingham, Birmingham, AL, USA

Zechen Chong

Division of Medical Oncology, National Cancer Centre, Singapore, Singapore

Su Pin Choo

Medical Oncology, University and Hospital Trust of Verona, Verona, Italy

Sara Cingarlini & Michele Milella

Department of Pediatrics, University Hospital Schleswig-Holstein, Kiel, Germany

Alexander Claviez

Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, ON, Canada

Sean Cleary, Ashton A. Connor & Steven Gallinger

School of Biological Sciences, University of Auckland, Auckland, New Zealand

Nicole Cloonan

Department of Surgery, University of Melbourne, Parkville, VIC, Australia

Marek Cmero

The Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC, Australia

Walter and Eliza Hall Institute, Parkville, VIC, Australia

Vancouver Prostate Centre, Vancouver, Canada

Colin C. Collins, Nilgun Donmez, Faraz Hach, Salem Malikic, S. Cenk Sahinalp, Iman Sarrafi & Raunak Shrestha

Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada

Ashton A. Connor, Steven Gallinger, Robert C. Grant, Treasa A. McPherson & Iris Selander

University of East Anglia, Norwich, UK

Colin S. Cooper

Norfolk and Norwich University Hospital NHS Trust, Norwich, UK

Matthew G. Cordes, Catrina C. Fronick & Tom Roques

Victorian Institute of Forensic Medicine, Southbank, VIC, Australia

Stephen M. Cordner

Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA

Isidro Cortés-Ciriano, Jake June-Koo Lee & Peter J. Park

Department of Chemistry, Centre for Molecular Science Informatics, University of Cambridge, Cambridge, UK

Isidro Cortés-Ciriano

Ludwig Center at Harvard Medical School, Boston, MA, USA

Kyle Covington, HarshaVardhan Doddapaneni, Richard A. Gibbs, Jianhong Hu, Joy C. Jayaseelan, Viktoriya Korchina, Lora Lewis, Donna M. Muzny, Linghua Wang, David A. Wheeler & Liu Xi

Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia

Prue A. Cowin, Anne Hamilton, Gisela Mir Arnau & Ravikiran Vedururu

Physics Division, Optimization and Systems Biology Lab, Massachusetts General Hospital, Boston, MA, USA

David Craft

Department of Medicine, Baylor College of Medicine, Houston, TX, USA

Chad J. Creighton

Yupeng Cun, Martin Peifer & Tsun-Po Yang

International Genomics Consortium, Phoenix, AZ, USA

Erin Curley & Troy Shelton

Genomics Research Program, Ontario Institute for Cancer Research, Toronto, ON, Canada

Karolina Czajka, Jenna Eagles, Thomas J. Hudson, Jeremy Johns, Faridah Mbabaali, John D. McPherson, Jessica K. Miller, Danielle Pasternack, Michelle Sam & Lee E. Timms

Barking Havering and Redbridge University Hospitals NHS Trust, Romford, UK

Bogdan Czerniak, Adel El-Naggar & David Khoo

Children’s Hospital at Westmead, University of Sydney, Sydney, NSW, Australia

Rebecca A. Dagg

Department of Medicine, Section of Endocrinology, University and Hospital Trust of Verona, Verona, Italy

Maria Vittoria Davi

Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Natalie R. Davidson, Andre Kahles, Kjong-Van Lehmann, Alessandro Pastore, Gunnar Rätsch, Chris Sander, Yasin Senbabaoglu & Nicholas D. Socci

Department of Biology, ETH Zurich, Zürich, Switzerland

Natalie R. Davidson, Andre Kahles, Kjong-Van Lehmann, Gunnar Rätsch & Stefan G. Stark

Department of Computer Science, ETH Zurich, Zurich, Switzerland

Natalie R. Davidson, Andre Kahles, Kjong-Van Lehmann & Gunnar Rätsch

SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland

Weill Cornell Medical College, New York, NY, USA

Natalie R. Davidson, Bishoy M. Faltas & Gunnar Rätsch

Academic Department of Medical Genetics, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK

Helen Davies & Serena Nik-Zainal

MRC Cancer Unit, University of Cambridge, Cambridge, UK

Helen Davies, Rebecca C. Fitzgerald, Nicola Grehan, Serena Nik-Zainal & Maria O’Donovan

Departments of Pediatrics and Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Ian J. Davis

Seven Bridges Genomics, Charlestown, MA, USA

Brandi N. Davis-Dusenbery, Sinisa Ivkovic, Milena Kovacevic, Ana Mijalkovic Lazic, Sanja Mijalkovic, Mia Nastic, Petar Radovic & Nebojsa Tijanic

Annai Systems, Inc, Carlsbad, CA, USA

Francisco M. De La Vega, Tal Shmaya & Dai-Ying Wu

Department of Pathology, General Hospital of Treviso, Department of Medicine, University of Padua, Treviso, Italy

Angelo P. Dei Tos

Department of Computational Biology, University of Lausanne, Lausanne, Switzerland

Olivier Delaneau

Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, CH, Switzerland

Swiss Institute of Bioinformatics, University of Geneva, Geneva, CH, Switzerland

Jonas Demeulemeester, Stefan C. Dentro, Matthew W. Fittall, Kerstin Haase, Clemency Jolly, Maxime Tarabichi & Peter Van Loo

Jonas Demeulemeester & Peter Van Loo

Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany

German M. Demidov, Francesc Muyas & Stephan Ossowski

Computational and Systems Biology, Genome Institute of Singapore, Singapore, Singapore

Deniz Demircioğlu & Jonathan Göke

School of Computing, National University of Singapore, Singapore, Singapore

Deniz Demircioğlu

Big Data Institute, Li Ka Shing Centre, University of Oxford, Oxford, UK

Stefan C. Dentro & David C. Wedge

Biomedical Data Science Laboratory, Francis Crick Institute, London, UK

Nikita Desai

Bioinformatics Group, Department of Computer Science, University College London, London, UK

The Edward S. Rogers Sr. Department of Electrical and Computer Engineering, University of Toronto, Toronto, ON, Canada

Amit G. Deshwar

Breast Cancer Translational Research Laboratory JC Heuson, Institut Jules Bordet, Brussels, Belgium

Christine Desmedt

Department of Oncology, Laboratory for Translational Breast Cancer Research, KU Leuven, Leuven, Belgium

Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain

Jordi Deu-Pons, Joan Frigola, Abel Gonzalez-Perez, Ferran Muiños, Loris Mularoni, Oriol Pich, Iker Reyes-Salazar, Carlota Rubio-Perez, Radhakrishnan Sabarinathan & David Tamborero

Research Program on Biomedical Informatics, Universitat Pompeu Fabra, Barcelona, Spain

Jordi Deu-Pons, Abel Gonzalez-Perez, Ferran Muiños, Loris Mularoni, Oriol Pich, Carlota Rubio-Perez, Radhakrishnan Sabarinathan & David Tamborero

Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada

Neesha C. Dhani, David Hedley & Malcolm J. Moore

Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA

Priyanka Dhingra, Ekta Khurana, Eric Minwei Liu & Alexander Martinez-Fundichely

Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA

Department of Pathology, UPMC Shadyside, Pittsburgh, PA, USA

Independent Consultant, Wellesley, USA

Anthony DiBiase

Department of Cell and Molecular Biology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

Klev Diamanti, Jan Komorowski & Husen M. Umer

Department of Medicine and Department of Genetics, Washington University School of Medicine, St. Louis, St. Louis, MO, USA

Li Ding, Robert S. Fulton, Michael D. McLellan, Michael C. Wendl & Venkata D. Yellapantula

Hefei University of Technology, Anhui, China

Shuai Ding & Shanlin Yang

Translational Cancer Research Unit, GZA Hospitals St.-Augustinus, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

Luc Dirix, Steven Van Laere, Gert G. Van den Eynden & Peter Vermeulen

Simon Fraser University, Burnaby, BC, Canada

Nilgun Donmez, Ermin Hodzic, Salem Malikic, S. Cenk Sahinalp & Iman Sarrafi

University of Pennsylvania, Philadelphia, PA, USA

Ronny Drapkin

Faculty of Science and Technology, University of Vic—Central University of Catalonia (UVic-UCC), Vic, Spain

Ana Dueso-Barroso

The Wellcome Trust, London, UK

Michael Dunn

The Hospital for Sick Children, Toronto, ON, Canada

Lewis Jonathan Dursi

Department of Pathology, Queen Elizabeth University Hospital, Glasgow, UK

Fraser R. Duthie

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia

Ken Dutton-Regester, Nicholas K. Hayward, Oliver Holmes, Peter A. Johansson, Stephen H. Kazakoff, Conrad R. Leonard, Felicity Newell, Katia Nones, Ann-Marie Patch, John V. Pearson, Antonia L. Pritchard, Michael C. Quinn, Paresh Vyas, Nicola Waddell, Scott Wood & Qinying Xu

Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK

Douglas F. Easton

Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK

Prostate Cancer Canada, Toronto, ON, Canada

Stuart Edmonds

Paul A. Edwards, Anthony R. Green, Andy G. Lynch, Florian Markowetz & Thomas J. Mitchell

Department of Laboratory Medicine, Translational Cancer Research, Lund University Cancer Center at Medicon Village, Lund University, Lund, Sweden

Anna Ehinger

Juergen Eils, Roland Eils & Daniel Hübschmann

New BIH Digital Health Center, Berlin Institute of Health (BIH) and Charité - Universitätsmedizin Berlin, Berlin, Germany

Juergen Eils, Roland Eils & Chris Lawerenz

CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain

Georgia Escaramis

Research Group on Statistics, Econometrics and Health (GRECS), UdG, Barcelona, Spain

Quantitative Genomics Laboratories (qGenomics), Barcelona, Spain

Xavier Estivill

Icelandic Cancer Registry, Icelandic Cancer Society, Reykjavik, Iceland

Jorunn E. Eyfjord, Holmfridur Hilmarsdottir & Jon G. Jonasson

State Key Laboratory of Cancer Biology, and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Shaanxi, China

Daiming Fan & Yongzhan Nie

Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy

Matteo Fassan

Rigshospitalet, Copenhagen, Denmark

Francesco Favero

Center for Cancer Genomics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Martin L. Ferguson

Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, QC, Canada

Vincent Ferretti

Australian Institute of Tropical Health and Medicine, James Cook University, Douglas, QLD, Australia

Matthew A. Field

Department of Neuro-Oncology, Istituto Neurologico Besta, Milano, Italy

Gaetano Finocchiaro

Bioplatforms Australia, North Ryde, NSW, Australia

Anna Fitzgerald & Catherine A. Shang

Department of Pathology (Research), University College London Cancer Institute, London, UK

Adrienne M. Flanagan

Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada

Neil E. Fleshner

Department of Medical Oncology, Josephine Nefkens Institute and Cancer Genomics Centre, Erasmus Medical Center, Rotterdam, CN, The Netherlands

John A. Foekens, John W. M. Martens, F. Germán Rodríguez-González, Anieta M. Sieuwerts & Marcel Smid

The University of Queensland Thoracic Research Centre, The Prince Charles Hospital, Brisbane, QLD, Australia

Kwun M. Fong

CIBIO/InBIO - Research Center in Biodiversity and Genetic Resources, Universidade do Porto, Vairão, Portugal

Nuno A. Fonseca

HCA Laboratories, London, UK

Christopher S. Foster

University of Liverpool, Liverpool, UK

The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel

Milana Frenkel-Morgenstern

Department of Neurosurgery, University of Florida, Gainesville, FL, USA

William Friedman

Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

Masashi Fukayama & Tetsuo Ushiku

University of Milano Bicocca, Monza, Italy

Carlo Gambacorti-Passerini

BGI-Shenzhen, Shenzhen, China

Shengjie Gao, Yong Hou, Chang Li, Lin Li, Siliang Li, Xiaobo Li, Xinyue Li, Dongbing Liu, Xingmin Liu, Qiang Pan-Hammarström, Hong Su, Jian Wang, Kui Wu, Heng Xiong, Huanming Yang, Chen Ye, Xiuqing Zhang, Yong Zhou & Shida Zhu

Department of Pathology, Oslo University Hospital Ulleval, Oslo, Norway

Øystein Garred

Center for Biomedical Informatics, Harvard Medical School, Boston, MA, USA

Nils Gehlenborg

Department Biochemistry and Molecular Biomedicine, University of Barcelona, Barcelona, Spain

Josep L. L. Gelpi

Office of Cancer Genomics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Daniela S. Gerhard

Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Clarissa Gerhauser, Christoph Plass & Dieter Weichenhan

Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Jeffrey E. Gershenwald

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Department of Computer Science, Yale University, New Haven, CT, USA

Mark Gerstein & Fabio C. P. Navarro

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA

Mark Gerstein, Sushant Kumar, Lucas Lochovsky, Shaoke Lou, Patrick D. McGillivray, Fabio C. P. Navarro, Leonidas Salichos & Jonathan Warrell

Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA

Mark Gerstein, Arif O. Harmanci, Sushant Kumar, Donghoon Lee, Shantao Li, Xiaotong Li, Lucas Lochovsky, Shaoke Lou, William Meyerson, Leonidas Salichos, Jonathan Warrell, Jing Zhang & Yan Zhang

Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA

Gad Getz & Paz Polak

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Ronald Ghossein, Dilip D. Giri, Christine A. Iacobuzio-Donahue, Jorge Reis-Filho & Victor Reuter

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA

Nasra H. Giama, Catherine D. Moser & Lewis R. Roberts

University of Sydney, Sydney, NSW, Australia

Anthony J. Gill & James G. Kench

University of Oxford, Oxford, UK

Pelvender Gill, Freddie C. Hamdy, Katalin Karaszi, Adam Lambert, Luke Marsden, Clare Verrill & Paresh Vyas

Department of Surgery, Academic Urology Group, University of Cambridge, Cambridge, UK

Vincent J. Gnanapragasam

Department of Medicine II, University of Würzburg, Wuerzburg, Germany

Maria Elisabeth Goebler

Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA

Carmen Gomez

Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain

Abel Gonzalez-Perez

Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), Durham, NC, USA

Dmitry A. Gordenin & Natalie Saini

St. Thomas’s Hospital, London, UK

James Gossage

Osaka International Cancer Center, Osaka, Japan

Kunihito Gotoh

Department of Pathology, Skåne University Hospital, Lund University, Lund, Sweden

Dorthe Grabau

Department of Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, UK

Janet S. Graham

National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

Eric Green, Carolyn M. Hutter & Heidi J. Sofia

Centre for Cancer Research, Victorian Comprehensive Cancer Centre, University of Melbourne, Melbourne, VIC, Australia

Sean M. Grimmond

Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA

Robert L. Grossman

German Center for Infection Research (DZIF), Partner Site Hamburg-Borstel-Lübeck-Riems, Hamburg, Germany

Adam Grundhoff

Bioinformatics Research Centre (BiRC), Aarhus University, Aarhus, Denmark

Qianyun Guo, Asger Hobolth & Jakob Skou Pedersen

Department of Biotechnology, Ministry of Science and Technology, Government of India, New Delhi, Delhi, India

Shailja Gupta & K. VijayRaghavan

National Cancer Centre Singapore, Singapore, Singapore

Jonathan Göke

Brandeis University, Waltham, MA, USA

James E. Haber

Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada

Department of Internal Medicine, Stanford University, Stanford, CA, USA

Mark P. Hamilton

The University of Texas Health Science Center at Houston, Houston, TX, USA

Leng Han, Yang Yang & Xuanping Zhang

Imperial College NHS Trust, Imperial College, London, INY, UK

George B. Hanna

Senckenberg Institute of Pathology, University of Frankfurt Medical School, Frankfurt, Germany

Martin Hansmann

Department of Medicine, Division of Biomedical Informatics, UC San Diego School of Medicine, San Diego, CA, USA

Olivier Harismendy

Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center, Houston, TX, USA

Arif O. Harmanci

Oxford Nanopore Technologies, New York, NY, USA

Eoghan Harrington & Sissel Juul

Institute of Medical Science, University of Tokyo, Tokyo, Japan

Takanori Hasegawa, Shuto Hayashi, Seiya Imoto, Mitsuhiro Komura, Satoru Miyano, Naoki Miyoshi, Kazuhiro Ohi, Eigo Shimizu, Yuichi Shiraishi, Hiroko Tanaka & Rui Yamaguchi

Howard Hughes Medical Institute, University of California Santa Cruz, Santa Cruz, CA, USA

David Haussler

Wakayama Medical University, Wakayama, Japan

Shinya Hayami, Masaki Ueno & Hiroki Yamaue

Department of Internal Medicine, Division of Medical Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

D. Neil Hayes

University of Tennessee Health Science Center for Cancer Research, Memphis, TN, USA

Department of Histopathology, Salford Royal NHS Foundation Trust, Salford, UK

Stephen J. Hayes

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

BIOPIC, ICG and College of Life Sciences, Peking University, Beijing, China

Yao He & Zemin Zhang

Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China

Children’s Hospital of Philadelphia, Philadelphia, PA, USA

Allison P. Heath

Department of Bioinformatics and Computational Biology and Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Apurva M. Hegde, Yiling Lu & John N. Weinstein

Karolinska Institute, Stockholm, Sweden

Eva Hellstrom-Lindberg & Jesper Lagergren

The Donnelly Centre, University of Toronto, Toronto, ON, Canada

Mohamed Helmy & Jeffrey A. Wintersinger

Department of Medical Genetics, College of Medicine, Hallym University, Chuncheon, South Korea

Seong Gu Heo, Eun Pyo Hong & Ji Wan Park

Department of Experimental and Health Sciences, Institute of Evolutionary Biology (UPF-CSIC), Universitat Pompeu Fabra, Barcelona, Spain

José María Heredia-Genestar, Tomas Marques-Bonet & Arcadi Navarro

Health Data Science Unit, University Clinics, Heidelberg, Germany

Carl Herrmann

Massachusetts General Hospital Center for Cancer Research, Charlestown, MA, USA

Julian M. Hess & Yosef E. Maruvka

Hokkaido University, Sapporo, Japan

Satoshi Hirano & Toru Nakamura

Department of Pathology and Clinical Laboratory, National Cancer Center Hospital, Tokyo, Japan

Nobuyoshi Hiraoka

Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Katherine A. Hoadley & Tara J. Skelly

Computational Biology, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany

Steve Hoffmann

University of Melbourne Centre for Cancer Research, Melbourne, VIC, Australia

Oliver Hofmann

University of Nebraska Medical Center, Omaha, NE, USA

Michael A. Hollingsworth & Sarah P. Thayer

Syntekabio Inc, Daejeon, South Korea

Jongwhi H. Hong

Department of Pathology, Academic Medical Center, Amsterdam, AZ, The Netherlands

Gerrit K. Hooijer

China National GeneBank-Shenzhen, Shenzhen, China

Yong Hou, Chang Li, Siliang Li, Xiaobo Li, Dongbing Liu, Xingmin Liu, Henk G. Stunnenberg, Hong Su, Kui Wu, Heng Xiong, Chen Ye & Shida Zhu

Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Volker Hovestadt, Murat Iskar, Peter Lichter, Bernhard Radlwimmer & Marc Zapatka

Division of Life Science and Applied Genomics Center, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China

Taobo Hu, Yogesh Kumar, Eric Z. Ma, Zhenggang Wu & Hong Xue

Icahn School of Medicine at Mount Sinai, New York, NY, USA

Kuan-lin Huang

Geneplus-Shenzhen, Shenzhen, China

School of Computer Science and Technology, Xi’an Jiaotong University, Xi’an, China

Yi Huang, Jiayin Wang, Xiao Xiao & Xuanping Zhang

AbbVie, North Chicago, IL, USA

Thomas J. Hudson

Institute of Pathology, Charité – University Medicine Berlin, Berlin, Germany

Michael Hummel & Dido Lenze

Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, BC, Canada

David Huntsman

Edinburgh Royal Infirmary, Edinburgh, UK

Ted R. Hupp

Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany

Matthew R. Huska, Julia Markowski & Roland F. Schwarz

Department of Pediatric Immunology, Hematology and Oncology, University Hospital, Heidelberg, Germany

Daniel Hübschmann

Daniel Hübschmann, Christof von Kalle & Roland F. Schwarz

Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany

Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY, USA

Marcin Imielinski

Marcin Imielinski & Xiaotong Yao

Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

William B. Isaacs

Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Shumpei Ishikawa, Hiroto Katoh & Daisuke Komura

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

Michael Ittmann

Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA

Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA

Technical University of Denmark, Lyngby, Denmark

Jose M. G. Izarzugaza

Department of Pathology, College of Medicine, Hanyang University, Seoul, South Korea

Jocelyne Jacquemier, Hyung-Yong Kim & Gu Kong

Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK

Nigel B. Jamieson

Department of Pathology, Asan Medical Center, College of Medicine, Ulsan University, Songpa-gu, Seoul, South Korea

Se Jin Jang & Hee Jin Lee

Science Writer, Garrett Park, MD, USA

Karine Jegalian

International Cancer Genome Consortium (ICGC)/ICGC Accelerating Research in Genomic Oncology (ARGO) Secretariat, Ontario Institute for Cancer Research, Toronto, ON, Canada

Jennifer L. Jennings

Lara Jerman

Department of Public Health Sciences, University of Chicago, Chicago, IL, USA

Research Institute, NorthShore University HealthSystem, Evanston, IL, USA

Department for Biomedical Research, University of Bern, Bern, Switzerland

Rory Johnson, Andrés Lanzós & Mark A. Rubin

Centre of Genomics and Policy, McGill University and Génome Québec Innovation Centre, Montreal, QC, Canada

Yann Joly, Bartha M. Knoppers, Mark Phillips & Adrian Thorogood

Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Corbin D. Jones

Hopp Children’s Cancer Center (KiTZ), Heidelberg, Germany

David T. W. Jones, Marcel Kool & Stefan M. Pfister

Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany

David T. W. Jones

Cancer Research UK, London, UK

Nic Jones & David Scott

Indivumed GmbH, Hamburg, Germany

Hartmut Juhl

Genome Integration Data Center, Syntekabio, Inc, Daejeon, South Korea

Jongsun Jung

University Hospital Zurich, Zurich, Switzerland

Andre Kahles, Kjong-Van Lehmann & Gunnar Rätsch

Clinical Bioinformatics, Swiss Institute of Bioinformatics, Geneva, Switzerland

Abdullah Kahraman

Institute for Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland

Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland

Abdullah Kahraman & Christian von Mering

MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, UK

Vera B. Kaiser & Colin A. Semple

Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Beth Karlan

Department of Biology, Bioinformatics Group, Division of Molecular Biology, Faculty of Science, University of Zagreb, Zagreb, Croatia

Rosa Karlić

Department for Internal Medicine II, University Hospital Schleswig-Holstein, Kiel, Germany

Dennis Karsch & Michael Kneba

Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia

Karin S. Kassahn

Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan

Hitoshi Katai

Department of Bioinformatics, Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan

Mamoru Kato, Hirofumi Rokutan & Mihoko Saito-Adachi

A.A. Kharkevich Institute of Information Transmission Problems, Moscow, Russia

Marat D. Kazanov

Oncology and Immunology, Dmitry Rogachev National Research Center of Pediatric Hematology, Moscow, Russia

Skolkovo Institute of Science and Technology, Moscow, Russia

Department of Surgery, The George Washington University, School of Medicine and Health Science, Washington, DC, USA

Electron Kebebew

Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Melanoma Institute Australia, Macquarie University, Sydney, NSW, Australia

Richard F. Kefford

MIT Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA

Manolis Kellis

Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia

James G. Kench & Richard A. Scolyer

Cholangiocarcinoma Screening and Care Program and Liver Fluke and Cholangiocarcinoma Research Centre, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand

Narong Khuntikeo

Controlled Department and Institution, New York, NY, USA

Ekta Khurana

Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA

Ekta Khurana & Alexander Martinez-Fundichely

National Cancer Center, Gyeonggi, South Korea

Hark Kyun Kim

Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul, South Korea

Hyung-Lae Kim

Health Sciences Department of Biomedical Informatics, University of California San Diego, La Jolla, CA, USA

Research Core Center, National Cancer Centre Korea, Goyang-si, South Korea

Jong K. Kim

Department of Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, South Korea

Youngwook Kim

Samsung Genome Institute, Seoul, South Korea

Breast Oncology Program, Dana-Farber/Brigham and Women’s Cancer Center, Boston, MA, USA

Tari A. King

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Tari A. King & Samuel Singer

Division of Breast Surgery, Brigham and Women’s Hospital, Boston, MA, USA

Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences (NIEHS), Durham, NC, USA

Leszek J. Klimczak

Department of Clinical Science, University of Bergen, Bergen, Norway

Stian Knappskog & Ola Myklebost

Center For Medical Innovation, Seoul National University Hospital, Seoul, South Korea

Youngil Koh

Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea

Youngil Koh & Sung-Soo Yoon

Institute of Computer Science, Polish Academy of Sciences, Warsawa, Poland

Jan Komorowski

Functional and Structural Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Marcel Kool, Andrey Korshunov, Michael Koscher, Stefan M. Pfister & Qi Wang

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, , National Institutes of Health, Bethesda, MD, USA

Roelof Koster

Institute for Medical Informatics Statistics and Epidemiology, University of Leipzig, Leipzig, Germany

Markus Kreuz & Markus Loeffler

Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Savitri Krishnamurthy

Department of Hematology and Oncology, Georg-Augusts-University of Göttingen, Göttingen, Germany

Dieter Kube & Lorenz H. P. Trümper

Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany

Ralf Küppers

King’s College London and Guy’s and St. Thomas’ NHS Foundation Trust, London, UK

Jesper Lagergren

Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI, USA

Peter W. Laird

The University of Queensland Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia

Sunil R. Lakhani & Peter T. Simpson

Department of Pediatric Oncology and Hematology, University of Cologne, Cologne, Germany

Pablo Landgraf

University of Düsseldorf, Düsseldorf, Germany

Pablo Landgraf & Guido Reifenberger

Department of Pathology, Institut Jules Bordet, Brussels, Belgium

Denis Larsimont

Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden

Erik Larsson

Children’s Medical Research Institute, Sydney, NSW, Australia

Loretta M. S. Lau & Hilda A. Pickett

ILSbio, LLC Biobank, Chestertown, MD, USA

Division of Genetics and Genomics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

Eunjung Alice Lee

Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, South Korea

Jeong-Yeon Lee

Department of Statistics, University of California Santa Cruz, Santa Cruz, CA, USA

National Genotyping Center, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

Ming Ta Michael Lee

Department of Vertebrate Genomics/Otto Warburg Laboratory Gene Regulation and Systems Biology of Cancer, Max Planck Institute for Molecular Genetics, Berlin, Germany

Hans Lehrach, Hans-Jörg Warnatz & Marie-Laure Yaspo

McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada

Louis Letourneau

biobyte solutions GmbH, Heidelberg, Germany

Ivica Letunic

Gynecologic Oncology, NYU Laura and Isaac Perlmutter Cancer Center, New York University, New York, NY, USA

Douglas A. Levine

Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, St. Louis, MO, USA

Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Harvard University, Cambridge, MA, USA

Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

W. M. Linehan

University of Oslo, Oslo, Norway

Ole Christian Lingjærde & Torill Sauer

University of Toronto, Toronto, ON, Canada

Fei-Fei Fei Liu, Quaid D. Morris, Ruian Shi, Shankar Vembu & Fan Yang

Peking University, Beijing, China

Fenglin Liu, Fan Zhang, Liangtao Zheng & Xiuqing Zheng

School of Life Sciences, Peking University, Beijing, China

Fenglin Liu

Leidos Biomedical Research, Inc, McLean, VA, USA

Hematology, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain

Armando Lopez-Guillermo

Second Military Medical University, Shanghai, China

Yong-Jie Lu & Hongwei Zhang

Chinese Cancer Genome Consortium, Shenzhen, China

Department of Medical Oncology, Beijing Hospital, Beijing, China

Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China

Youyong Lu & Rui Xing

School of Medicine/School of Mathematics and Statistics, University of St. Andrews, St, Andrews, Fife, UK

Andy G. Lynch

Institute for Systems Biology, Seattle, WA, USA

Lisa Lype, Sheila M. Reynolds & Ilya Shmulevich

Department of Biochemistry and Molecular Biology, Faculty of Medicine, University Institute of Oncology-IUOPA, Oviedo, Spain

Carlos López-Otín & Xose S. Puente

Institut Bergonié, Bordeaux, France

Gaetan MacGrogan

Cancer Unit, MRC University of Cambridge, Cambridge, UK

Shona MacRae

Department of Pathology and Laboratory Medicine, Center for Personalized Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, USA

Dennis T. Maglinte

John Curtin School of Medical Research, Canberra, ACT, Australia

Graham J. Mann

MVZ Department of Oncology, PraxisClinic am Johannisplatz, Leipzig, Germany

Luisa Mantovani-Löffler

Department of Information Technology, Ghent University, Ghent, Belgium

Kathleen Marchal & Sergio Pulido-Tamayo

Department of Plant Biotechnology and Bioinformatics, Ghent University, Ghent, Belgium

Kathleen Marchal, Sergio Pulido-Tamayo & Lieven P. C. Verbeke

Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, USA

Elaine R. Mardis

Computational Biology Program, School of Medicine, Oregon Health and Science University, Portland, OR, USA

Adam A. Margolin & Adam J. Struck

Department of Surgery, Duke University, Durham, NC, USA

Jeffrey Marks

Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

Tomas Marques-Bonet, Jose I. Martin-Subero, Arcadi Navarro, David Torrents & Alfonso Valencia

Institut Català de Paleontologia Miquel Crusafont, Universitat Autònoma de Barcelona, Barcelona, Spain

Tomas Marques-Bonet

Sancha Martin & Ke Yuan

Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

Jose I. Martin-Subero

Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA

R. Jay Mashl

Department of Surgery and Cancer, Imperial College, London, INY, UK

Applications Department, Oxford Nanopore Technologies, Oxford, UK

Simon Mayes & Daniel J. Turner

Department of Obstetrics, Gynecology and Reproductive Services, University of California San Francisco, San Francisco, CA, USA

Karen McCune & Karen Smith-McCune

Department of Biochemistry and Molecular Medicine, University California at Davis, Sacramento, CA, USA

John D. McPherson

STTARR Innovation Facility, Princess Margaret Cancer Centre, Toronto, ON, Canada

Discipline of Surgery, Western Sydney University, Penrith, NSW, Australia

Neil D. Merrett

Yale School of Medicine, Yale University, New Haven, CT, USA

William Meyerson

Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Piotr A. Mieczkowski, Joel S. Parker, Charles M. Perou, Donghui Tan, Umadevi Veluvolu & Matthew D. Wilkerson

Departments of Neurology and Neurosurgery, Henry Ford Hospital, Detroit, MI, USA

Tom Mikkelsen

Precision Oncology, OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA

Gordon B. Mills

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Sarah Minner, Guido Sauter & Ronald Simon

Department of Health Sciences, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan

Shinichi Mizuno

Heidelberg Academy of Sciences and Humanities, Heidelberg, Germany

Fruzsina Molnár-Gábor

Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia

Carl Morrison, Karin A. Oien, Chawalit Pairojkul, Paul M. Waring & Marc J. van de Vijver

Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA

Carl Morrison

Department of Computer Science, University of Helsinki, Helsinki, Finland

Ville Mustonen

Institute of Biotechnology, University of Helsinki, Helsinki, Finland

Organismal and Evolutionary Biology Research Programme, University of Helsinki, Helsinki, Finland

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, MO, USA

David Mutch

Penrose St. Francis Health Services, Colorado Springs, CO, USA

Jerome Myers

Institute of Pathology, Ulm University and University Hospital of Ulm, Ulm, Germany

Peter Möller

National Cancer Center, Tokyo, Japan

Hitoshi Nakagama

Genome Institute of Singapore, Singapore, Singapore

Tannistha Nandi & Patrick Tan

32Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA

Fabio C. P. Navarro

German Cancer Aid, Bonn, Germany

Gerd Nettekoven & Laura Planko

Programme in Cancer and Stem Cell Biology, Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore

Alvin Wei Tian Ng

The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China

Fourth Military Medical University, Shaanxi, China

Yongzhan Nie

The University of Cambridge School of Clinical Medicine, Cambridge, UK

Serena Nik-Zainal

St. Jude Children’s Research Hospital, Memphis, TN, USA

Paul A. Northcott

University Health Network, Princess Margaret Cancer Centre, Toronto, ON, Canada

Faiyaz Notta & Ming Tsao

Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, CA, USA

Brian D. O’Connor

Department of Medicine, University of Chicago, Chicago, IL, USA

Peter O’Donnell

Department of Neurology, Mayo Clinic, Rochester, MN, USA

Brian Patrick O’Neill

Cambridge Oesophagogastric Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

J. Robert O’Neill

Institute of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

Karin A. Oien

Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA

Akinyemi I. Ojesina

HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA

O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA

Department of Pathology, Keio University School of Medicine, Tokyo, Japan

Hidenori Ojima

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan

Takuji Okusaka

Sage Bionetworks, Seattle, WA, USA

Larsson Omberg

Lymphoma Genomic Translational Research Laboratory, National Cancer Centre, Singapore, Singapore

Choon Kiat Ong

Department of Clinical Pathology, Robert-Bosch-Hospital, Stuttgart, Germany

Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada

B. F. Francis Ouellette

Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

Qiang Pan-Hammarström

Center for Liver Cancer, Research Institute and Hospital, National Cancer Center, Gyeonggi, South Korea

Joong-Won Park

Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

Keunchil Park

Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, South Korea

Cheonan Industry-Academic Collaboration Foundation, Sangmyung University, Cheonan, South Korea

Kiejung Park

NYU Langone Medical Center, New York, NY, USA

Harvey Pass

Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, USA

Nathan A. Pennell

Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA

Marc D. Perry

Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

Gloria M. Petersen

Helen F. Graham Cancer Center at Christiana Care Health Systems, Newark, DE, USA

Nicholas Petrelli

Heidelberg University Hospital, Heidelberg, Germany

Stefan M. Pfister

CSRA Incorporated, Fairfax, VA, USA

Todd D. Pihl

Research Department of Pathology, University College London Cancer Institute, London, UK

Nischalan Pillay

Department of Research Oncology, Guy’s Hospital, King’s Health Partners AHSC, King’s College London School of Medicine, London, UK

Sarah Pinder

Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia

Andreia V. Pinho

University Hospital of Minjoz, INSERM UMR 1098, Besançon, France

Xavier Pivot

Spanish National Cancer Research Centre, Madrid, Spain

Center of Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania

Irinel Popescu

Cureline, Inc, South San Francisco, CA, USA

Olga Potapova

St. Luke’s Cancer Centre, Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK

Shaun R. Preston

Cambridge Breast Unit, Addenbrooke’s Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge, UK

Elena Provenzano

East of Scotland Breast Service, Ninewells Hospital, Aberdeen, UK

Colin A. Purdie

Department of Genetics, Microbiology and Statistics, University of Barcelona, IRSJD, IBUB, Barcelona, Spain

Raquel Rabionet

Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA

Janet S. Rader

Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA

Suresh Ramalingam

Benjamin J. Raphael & Matthew A. Reyna

Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA

W. Kimryn Rathmell

Ohio State University College of Medicine and Arthur G. James Comprehensive Cancer Center, Columbus, OH, USA

Matthew Ringel

Department of Surgery, Yokohama City University Graduate School of Medicine, Kanagawa, Japan

Yasushi Rino

Division of Chromatin Networks, German Cancer Research Center (DKFZ) and BioQuant, Heidelberg, Germany

Karsten Rippe

Research Computing Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Jeffrey Roach

School of Molecular Biosciences and Center for Reproductive Biology, Washington State University, Pullman, WA, USA

Steven A. Roberts

Finsen Laboratory and Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark

F. Germán Rodríguez-González, Nikos Sidiropoulos & Joachim Weischenfeldt

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

Michael H. A. Roehrl & Stefano Serra

Department of Pathology, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Michael H. A. Roehrl

University Hospital Giessen, Pediatric Hematology and Oncology, Giessen, Germany

Marius Rohde

Oncologie Sénologie, ICM Institut Régional du Cancer, Montpellier, France

Gilles Romieu

Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany

Philip C. Rosenstiel & Markus B. Schilhabel

Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany

Andreas Rosenwald

Department of Urology, North Bristol NHS Trust, Bristol, UK

Edward W. Rowe

SingHealth, Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore, Singapore

Steven G. Rozen, Patrick Tan & Bin Tean Teh

Department of Computer Science, University of Toronto, Toronto, ON, Canada

Yulia Rubanova, Jared T. Simpson & Jeffrey A. Wintersinger

Bern Center for Precision Medicine, University Hospital of Bern, University of Bern, Bern, Switzerland

Mark A. Rubin

Englander Institute for Precision Medicine, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY, USA

Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA

Pathology and Laboratory, Weill Cornell Medical College, New York, NY, USA

Vall d’Hebron Institute of Oncology: VHIO, Barcelona, Spain

Carlota Rubio-Perez

General and Hepatobiliary-Biliary Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy

Andrea Ruzzenente

National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India

Radhakrishnan Sabarinathan

S. Cenk Sahinalp

Department of Pathology, GZA-ZNA Hospitals, Antwerp, Belgium

Roberto Salgado

Analytical Biological Services, Inc, Wilmington, DE, USA

Charles Saller

Sydney Medical School, University of Sydney, Sydney, NSW, Australia

Jaswinder S. Samra & Richard A. Scolyer

cBio Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

Chris Sander & Ciyue Shen

Department of Cell Biology, Harvard Medical School, Boston, MA, USA

Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, Maharashtra, India

Rajiv Sarin

School of Environmental and Life Sciences, Faculty of Science, The University of Newcastle, Ourimbah, NSW, Australia

Christopher J. Scarlett

Department of Dermatology, University Hospital of Essen, Essen, Germany

Dirk Schadendorf

Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Matthias Schlesner

Department of Urology, Charité Universitätsmedizin Berlin, Berlin, Germany

Thorsten Schlomm & Joachim Weischenfeldt

Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Thorsten Schlomm

Department of General Internal Medicine, University of Kiel, Kiel, Germany

Stefan Schreiber

German Cancer Consortium (DKTK), Partner site Berlin, Berlin, Germany

Roland F. Schwarz

Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA

Ralph Scully

University of Pittsburgh, Pittsburgh, PA, USA

Raja Seethala

Department of Ophthalmology and Ocular Genomics Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA

Ayellet V. Segre

Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL, USA

Subhajit Sengupta

Van Andel Research Institute, Grand Rapids, MI, USA

Hui Shen & Wanding Zhou

Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan

Tatsuhiro Shibata, Hirokazu Taniguchi & Tomoko Urushidate

Japan Agency for Medical Research and Development, Tokyo, Japan

Kiyo Shimizu & Takashi Yugawa

Seung Jun Shin & Stefan G. Stark

Murtha Cancer Center, Walter Reed National Military Medical Center, Bethesda, MD, USA

Craig Shriver

Human Genetics, University of Kiel, Kiel, Germany

Reiner Siebert

Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

Sabina Signoretti

Oregon Health and Science University, Portland, OR, USA

Jaclyn Smith

Center for RNA Interference and Noncoding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Anil K. Sood

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK

Sharmila Sothi

Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, GA, The Netherlands

Paul N. Span

Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL, USA

Jonathan Spring

Clinic for Hematology and Oncology, St.-Antonius-Hospital, Eschweiler, Germany

Peter Staib

Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Stefan G. Stark

University of Iceland, Reykjavik, Iceland

Ólafur Andri Stefánsson

Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Oliver Stegle

Dundee Cancer Centre, Ninewells Hospital, Dundee, UK

Alasdair Stenhouse & Alastair M. Thompson

Department for Internal Medicine III, University of Ulm and University Hospital of Ulm, Ulm, Germany

Stephan Stilgenbauer

Institut Curie, INSERM Unit 830, Paris, France

Henk G. Stunnenberg & Anne Vincent-Salomon

Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan

Akihiro Suzuki

Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, GA, The Netherlands

Division of Cancer Genome Research, German Cancer Research Center (DKFZ), Heidelberg, Germany

Holger Sültmann

Department of General Surgery, Singapore General Hospital, Singapore, Singapore

Benita Kiat Tee Tan

Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore

Patrick Tan & Bin Tean Teh

Department of Medical and Clinical Genetics, Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland

Tomas J. Tanskanen

East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

Patrick Tarpey

Irving Institute for Cancer Dynamics, Columbia University, New York, NY, USA

Simon Tavaré

Institute of Molecular and Cell Biology, Singapore, Singapore

Bin Tean Teh

Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore, Singapore

Universite Lyon, INCa-Synergie, Centre Léon Bérard, Lyon, France

Gilles Thomas

Department of Urology, Mayo Clinic, Rochester, MN, USA

R. Houston Thompson

Royal National Orthopaedic Hospital - Stanmore, Stanmore, Middlesex, UK

Roberto Tirabosco

Department of Biochemistry, Genetics and Immunology, University of Vigo, Vigo, Spain

Giovanni Paolo II / I.R.C.C.S. Cancer Institute, Bari, BA, Italy

Stefania Tommasi

Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Umut H. Toprak

Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy, Rome, Italy

Giampaolo Tortora

University of Verona, Verona, Italy

Centre National de Génotypage, CEA - Institute de Génomique, Evry, France

CAPHRI Research School, Maastricht University, Maastricht, ER, The Netherlands

David Townend

Department of Biopathology, Centre Léon Bérard, Lyon, France

Isabelle Treilleux

Université Claude Bernard Lyon 1, Villeurbanne, France

Core Research for Evolutional Science and Technology (CREST), JST, Tokyo, Japan

Tatsuhiko Tsunoda

Department of Biological Sciences, Laboratory for Medical Science Mathematics, Graduate School of Science, University of Tokyo, Yokohama, Japan

Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

Cancer Ageing and Somatic Mutation Programme, Wellcome Sanger Institute, Hinxton, UK

Jose M. C. Tubio

University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

Olga Tucker

Centre for Cancer Research and Cell Biology, Queen’s University, Belfast, UK

Richard Turkington

Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Naoto T. Ueno

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Christopher Umbricht

Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden

Husen M. Umer

School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK

Timothy J. Underwood

Department of Gene Technology, Tallinn University of Technology, Tallinn, Estonia

Liis Uusküla-Reimand

Genetics and Genome Biology Program, SickKids Research Institute, The Hospital for Sick Children, Toronto, ON, Canada

Departments of Neurosurgery and Hematology and Medical Oncology, Winship Cancer Institute and School of Medicine, Emory University, Atlanta, GA, USA

Erwin G. Van Meir

Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway

Miguel Vazquez

Argmix Consulting, North Vancouver, BC, Canada

Shankar Vembu

Department of Information Technology, Ghent University, Interuniversitair Micro-Electronica Centrum (IMEC), Ghent, Belgium

Lieven P. C. Verbeke

Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK

Clare Verrill

Institute of Mathematics and Computer Science, University of Latvia, Riga, LV, Latvia

Juris Viksna

Discipline of Pathology, Sydney Medical School, University of Sydney, Sydney, NSW, Australia

Ricardo E. Vilain

Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK

Ignacio Vázquez-García

Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Ignacio Vázquez-García & Venkata D. Yellapantula

Department of Statistics, Columbia University, New York, NY, USA

Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

Claes Wadelius

School of Electronic and Information Engineering, Xi’an Jiaotong University, Xi’an, China

Jiayin Wang & Kai Ye

Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

Anne Y. Warren

Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK

David C. Wedge

Georgia Regents University Cancer Center, Augusta, GA, USA

Paul Weinberger

Wythenshawe Hospital, Manchester, UK

Department of Genetics, Washington University School of Medicine, St.Louis, MO, USA

Michael C. Wendl

Department of Biological Oceanography, Leibniz Institute of Baltic Sea Research, Rostock, Germany

Johannes Werner

Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK

Justin P. Whalley

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

Thoracic Oncology Laboratory, Mayo Clinic, Rochester, MN, USA

Dennis Wigle

Richard K. Wilson

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Mayo Clinic, Rochester, MN, USA

Boris Winterhoff

International Institute for Molecular Oncology, Poznań, Poland

Maciej Wiznerowicz

Poznan University of Medical Sciences, Poznań, Poland

Genomics and Proteomics Core Facility High Throughput Sequencing Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany

Stephan Wolf

NCCS-VARI Translational Research Laboratory, National Cancer Centre Singapore, Singapore, Singapore

Bernice H. Wong

Edison Family Center for Genome Sciences and Systems Biology, Washington University, St. Louis, MO, USA

Winghing Wong

MRC-University of Glasgow Centre for Virus Research, Glasgow, UK

Derek W. Wright

Department of Medical Informatics and Clinical Epidemiology, Division of Bioinformatics and Computational Biology, OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA

Guanming Wu

School of Electronic Information and Communications, Huazhong University of Science and Technology, Wuhan, China

Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD, USA

Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan

Shinichi Yachida

Institute of Computer Science, Heidelberg University, Heidelberg, Germany

Sergei Yakneen

School of Mathematics and Statistics, University of Sydney, Sydney, NSW, Australia

Jean Y. Yang

Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA

Lixing Yang

Department of Human Genetics, University of Chicago, Chicago, IL, USA

Tri-Institutional PhD Program in Computational Biology and Medicine, Weill Cornell Medicine, New York, NY, USA

Xiaotong Yao

The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China

Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Kaixian Yu & Hongtu Zhu

Duke-NUS Medical School, Singapore, Singapore

Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

School of Computing Science, University of Glasgow, Glasgow, UK

Division of Orthopaedic Surgery, Oslo University Hospital, Oslo, Norway

Olga Zaikova

Eastern Clinical School, Monash University, Melbourne, VIC, Australia

Nikolajs Zeps

Epworth HealthCare, Richmond, VIC, Australia

Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

Cheng-Zhong Zhang

Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA

The Ohio State University Comprehensive Cancer Center (OSUCCC – James), Columbus, OH, USA

The University of Texas School of Biomedical Informatics (SBMI) at Houston, Houston, TX, USA

Zhongming Zhao

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia

Anna deFazio

Department of Pathology, Erasmus Medical Center Rotterdam, Rotterdam, GD, The Netherlands

Carolien H. M. van Deurzen

Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, CX, The Netherlands

L. van’t Veer

Institute of Molecular Life Sciences and Swiss Institute of Bioinformatics, University of Zurich, Zurich, Switzerland

Christian von Mering

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• , Hyung-Lae Kim
• , Hyung-Yong Kim
• , Hyunghwan Kim
• , Jaegil Kim
• , Jihoon Kim
• , Jong K. Kim
• , Youngwook Kim
• , Tari A. King
• , Wolfram Klapper
• , Leszek J. Klimczak
• , Stian Knappskog
• , Michael Kneba
• , Bartha M. Knoppers
• , Youngil Koh
• , Jan Komorowski
• , Daisuke Komura
• , Mitsuhiro Komura
• , Marcel Kool
• , Jan O. Korbel
• , Viktoriya Korchina
• , Andrey Korshunov
• , Michael Koscher
• , Roelof Koster
• , Zsofia Kote-Jarai
• , Antonios Koures
• , Milena Kovacevic
• , Barbara Kremeyer
• , Helene Kretzmer
• , Markus Kreuz
• , Savitri Krishnamurthy
• , Dieter Kube
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• , Pardeep Kumar
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• , Yogesh Kumar
• , Ritika Kundra
• , Kirsten Kübler
• , Ralf Küppers
• , Jesper Lagergren
• , Phillip H. Lai
• , Peter W. Laird
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• , Adam Lambert
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• , Denis Larsimont
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• , Darlene Lee
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• , Eunjung Alice Lee
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• , Daniel A. Leongamornlert
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• , Lisle E. Mose
• , Catherine D. Moser
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• , Andrew J. Mungall
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• , Donna M. Muzny
• , Alfonso Muñoz
• , Jerome Myers
• , Ola Myklebost
• , Peter Möller
• , Genta Nagae
• , Adnan M. Nagrial
• , Hardeep K. Nahal-Bose
• , Hitoshi Nakagama
• , Hidewaki Nakagawa
• , Hiromi Nakamura
• , Toru Nakamura
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• , Tannistha Nandi
• , Jyoti Nangalia
• , Mia Nastic
• , Arcadi Navarro
• , Fabio C. P. Navarro
• , David E. Neal
• , Gerd Nettekoven
• , Felicity Newell
• , Steven J. Newhouse
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• , Alvin Wei Tian Ng
• , Anthony Ng
• , Jonathan Nicholson
• , David Nicol
• , Yongzhan Nie
• , G. Petur Nielsen
• , Morten Muhlig Nielsen
• , Serena Nik-Zainal
• , Michael S. Noble
• , Katia Nones
• , Paul A. Northcott
• , Faiyaz Notta
• , Brian D. O’Connor
• , Peter O’Donnell
• , Maria O’Donovan
• , Sarah O’Meara
• , Brian Patrick O’Neill
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• , David Ocana
• , Angelica Ochoa
• , Christopher Ogden
• , Hideki Ohdan
• , Kazuhiro Ohi
• , Lucila Ohno-Machado
• , Karin A. Oien
• , Akinyemi I. Ojesina
• , Hidenori Ojima
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• , Choon Kiat Ong
• , Stephan Ossowski
• , German Ott
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• , Chawalit Pairojkul
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• , Elli Papaemmanuil
• , Irene Papatheodorou
• , Nagarajan Paramasivam
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• , Joong-Won Park
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• , Kiejung Park
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• , Simon L. Parsons
• , Harvey Pass
• , Danielle Pasternack
• , Alessandro Pastore
• , Ann-Marie Patch
• , Iris Pauporté
• , Antonio Pea
• , John V. Pearson
• , Chandra Sekhar Pedamallu
• , Jakob Skou Pedersen
• , Paolo Pederzoli
• , Nathan A. Pennell
• , Charles M. Perou
• , Marc D. Perry
• , Gloria M. Petersen
• , Nicholas Petrelli
• , Robert Petryszak
• , Stefan M. Pfister
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• , Oriol Pich
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• , Todd D. Pihl
• , Nischalan Pillay
• , Sarah Pinder
• , Mark Pinese
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• , Paz Polak
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• , Steven A. Roberts
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• , Alan J. Robertson
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• , Bernardo Rodriguez-Martin
• , F. Germán Rodríguez-González
• , Michael H. A. Roehrl
• , Marius Rohde
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• , Philip C. Rosenstiel
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• , Romina Royo
• , Steven G. Rozen
• , Mark A. Rubin
• , Carlota Rubio-Perez
• , Vasilisa A. Rudneva
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• , Jaswinder S. Samra
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• , Grant Sanders
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• , Aya Sasaki-Oku
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• , Heather K. Schmidt
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• , Nikolaus Schultz
• , Steven E. Schumacher
• , Roland F. Schwarz
• , Richard A. Scolyer
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• , Yasin Senbabaoglu
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• , Catherine A. Shang
• , Ping Shang
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• , Kiyo Shimizu
• , Yuichi Shiraishi
• , Tal Shmaya
• , Ilya Shmulevich
• , Solomon I. Shorser
• , Charles Short
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• , Suyash S. Shringarpure
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• , Shimin Shuai
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• , Katarzyna O. Sikora
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• , Ronald Simon
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• , Peter T. Simpson
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• , Tara J. Skelly
• , Marcel Smid
• , Jaclyn Smith
• , Karen Smith-McCune
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• , Matthew G. Soloway
• , Anil K. Sood
• , Sharmila Sothi
• , Christos Sotiriou
• , Cameron M. Soulette
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• , Nicola Sperandio
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• , Jonathan Spring
• , Johan Staaf
• , Peter F. Stadler
• , Peter Staib
• , Stefan G. Stark
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• , Stephan Stilgenbauer
• , Miranda D. Stobbe
• , Michael R. Stratton
• , Jonathan R. Stretch
• , Adam J. Struck
• , Joshua M. Stuart
• , Henk G. Stunnenberg
• , Xiaoping Su
• , Ren X. Sun
• , Stephanie Sungalee
• , Hana Susak
• , Akihiro Suzuki
• , Fred Sweep
• , Monika Szczepanowski
• , Holger Sültmann
• , Takashi Yugawa
• , Angela Tam
• , David Tamborero
• , Benita Kiat Tee Tan
• , Donghui Tan
• , Patrick Tan
• , Hiroko Tanaka
• , Hirokazu Taniguchi
• , Tomas J. Tanskanen
• , Roy Tarnuzzer
• , Patrick Tarpey
• , Morgan L. Taschuk
• , Kenji Tatsuno
• , Simon Tavaré
• , Darrin F. Taylor
• , Amaro Taylor-Weiner
• , Jon W. Teague
• , Bin Tean Teh
• , Varsha Tembe
• , Javier Temes
• , Kevin Thai
• , Sarah P. Thayer
• , Nina Thiessen
• , Gilles Thomas
• , Sarah Thomas
• , Alan Thompson
• , Alastair M. Thompson
• , John F. F. Thompson
• , R. Houston Thompson
• , Heather Thorne
• , Leigh B. Thorne
• , Adrian Thorogood
• , Grace Tiao
• , Nebojsa Tijanic
• , Lee E. Timms
• , Roberto Tirabosco
• , Marta Tojo
• , Stefania Tommasi
• , Christopher W. Toon
• , Umut H. Toprak
• , David Torrents
• , Giampaolo Tortora
• , Jörg Tost
• , Yasushi Totoki
• , David Townend
• , Nadia Traficante
• , Isabelle Treilleux
• , Jean-Rémi Trotta
• , Lorenz H. P. Trümper
• , Ming Tsao
• , Tatsuhiko Tsunoda
• , Jose M. C. Tubio
• , Olga Tucker
• , Richard Turkington
• , Daniel J. Turner
• , Andrew Tutt
• , Masaki Ueno
• , Naoto T. Ueno
• , Christopher Umbricht
• , Husen M. Umer
• , Timothy J. Underwood
• , Lara Urban
• , Tomoko Urushidate
• , Tetsuo Ushiku
• , Liis Uusküla-Reimand
• , Alfonso Valencia
• , David J. Van Den Berg
• , Steven Van Laere
• , Peter Van Loo
• , Erwin G. Van Meir
• , Gert G. Van den Eynden
• , Theodorus Van der Kwast
• , Naveen Vasudev
• , Miguel Vazquez
• , Ravikiran Vedururu
• , Umadevi Veluvolu
• , Lieven P. C. Verbeke
• , Peter Vermeulen
• , Clare Verrill
• , Alain Viari
• , David Vicente
• , Caterina Vicentini
• , K. VijayRaghavan
• , Juris Viksna
• , Ricardo E. Vilain
• , Izar Villasante
• , Anne Vincent-Salomon
• , Tapio Visakorpi
• , Douglas Voet
• , Paresh Vyas
• , Nick M. Waddell
• , Nicola Waddell
• , Claes Wadelius
• , Lina Wadi
• , Rabea Wagener
• , Jeremiah A. Wala
• , Jian Wang
• , Jiayin Wang
• , Linghua Wang
• , Yumeng Wang
• , Zhining Wang
• , Paul M. Waring
• , Hans-Jörg Warnatz
• , Jonathan Warrell
• , Anne Y. Warren
• , Sebastian M. Waszak
• , Dieter Weichenhan
• , Paul Weinberger
• , John N. Weinstein
• , Joachim Weischenfeldt
• , Daniel J. Weisenberger
• , Ian Welch
• , Michael C. Wendl
• , Johannes Werner
• , Justin P. Whalley
• , Hayley C. Whitaker
• , Dennis Wigle
• , Matthew D. Wilkerson
• , Ashley Williams
• , James S. Wilmott
• , Gavin W. Wilson
• , Julie M. Wilson
• , Richard K. Wilson
• , Boris Winterhoff
• , Jeffrey A. Wintersinger
• , Maciej Wiznerowicz
• , Stephan Wolf
• , Bernice H. Wong
• , Tina Wong
• , Winghing Wong
• , Youngchoon Woo
• , Scott Wood
• , Bradly G. Wouters
• , Adam J. Wright
• , Derek W. Wright
• , Mark H. Wright
• , Chin-Lee Wu
• , Dai-Ying Wu
• , Guanming Wu
• , Jianmin Wu
• , Zhenggang Wu
• , Qian Xiang
• , Xiao Xiao
• , Heng Xiong
• , Qinying Xu
• , Yanxun Xu
• , Shinichi Yachida
• , Sergei Yakneen
• , Rui Yamaguchi
• , Takafumi N. Yamaguchi
• , Masakazu Yamamoto
• , Shogo Yamamoto
• , Hiroki Yamaue
• , Huanming Yang
• , Jean Y. Yang
• , Liming Yang
• , Lixing Yang
• , Shanlin Yang
• , Yang Yang
• , Marie-Laure Yaspo
• , Lucy Yates
• , Christina Yau
• , Venkata D. Yellapantula
• , Christopher J. Yoon
• , Sung-Soo Yoon
• , Fouad Yousif
• , Willie Yu
• , Yingyan Yu
• , Yuan Yuan
• , Denis Yuen
• , Christina K. Yung
• , Olga Zaikova
• , Jorge Zamora
• , Marc Zapatka
• , Jean C. Zenklusen
• , Thorsten Zenz
• , Nikolajs Zeps
• , Cheng-Zhong Zhang
• , Fan Zhang
• , Hailei Zhang
• , Hongwei Zhang
• , Hongxin Zhang
• , Jiashan Zhang
• , Jing Zhang
• , Junjun Zhang
• , Xiuqing Zhang
• , Xuanping Zhang
• , Yan Zhang
• , Zemin Zhang
• , Zhongming Zhao
• , Liangtao Zheng
• , Xiuqing Zheng
• , Wanding Zhou
• , Yong Zhou
• , Jingchun Zhu
• , Shida Zhu
• , Lihua Zou
• , Xueqing Zou
• , Anna deFazio
• , Nicholas van As
• , Carolien H. M. van Deurzen
• , Marc J. van de Vijver
• , L. van’t Veer
•  & Christian von Mering

Contributions

M.G., C.J., I.L., S.G., P.A., D.R., D.G.L., P.T.S. and P.V.L. performed timing of point mutations and copy number gains. S.G. and M.G. performed qualitative timing of driver point mutations and analyses of synchronous gains, L.J. timed secondary copy number gains. I.L., T.J.M., D.R., D.G.L., D.C.W. and G.G. performed relative timing of somatic driver events and implemented integrative models. C.J., Y.R., M.G., Q.D.M. and P.V.L. performed timing of mutational signatures. M.G. performed real-time estimation of whole-genome duplication and subclonal diversification. S.G. assessed mutation rates in relapsed samples. C.J., M.G., I.L., Y.R., D.R. and P.V.L. constructed cancer timelines. M.G., C.J., I.L., S.C.D., S.G., T.J.M., Y.R., P.A., J.D., P.C.B., D.D.B., V.M., Q.D.M., P.T.S., D.C.W. and P.V.L. interpreted the results. S.C.D., I.L., J.W., A.D., I.V.-G., K. Yuan, G.M., M.P., S.M., N.D., K. Yu, S. Sengupta, K.H., M.T., J.D., D.G.L., D.R., J.L., M.C., S.C.S., Y.J., F.M., V.M., H.Z., W.W., Q.D.M., D.C.W. and P.V.L. performed subclonal architecture analysis. S.C.D., I.L., K.K., V.M., M.P., X.Y., D.G.L., S. Schumacher, R.B., M.I., M.S., D.C.W. and P.V.L. performed copy number analysis. J.W., S.C.D., I.L., K.H., D.G.L., K.K., D.R., D.C.W., Q.D.M. and P.V.L. derived a consensus of copy number analysis results. K. Yu, M.T., A.D., S.C.D., I.L., D.C.W., M.G., P.V.L., Q.D.M. and W.W. derived a consensus of subclonal architecture results. Y.F. and W.W. contributed to subclonal mutation calls. P.T.S., D.C.W. and P.V.L. coordinated the study. M.G., C.J., P.T.S., Y.R., I.L., Q.D.M., D.C.W. and P.V.L. wrote the manuscript, which all authors approved. S.C.D., I.L., M.G., C.J., K.H., M.T., J.W., A.G.D., K. Yu, S.G., Y.R. and G.M. in the PCAWG Evolution & Heterogeneity Working Group contributed equally. W.W., Q.D.M., P.T.S., D.C.W. and P.V.L. in the PCAWG Evolution & Heterogeneity Working Group jointly supervised the work.

Corresponding authors

Correspondence to Moritz Gerstung or Peter Van Loo .

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Competing interests.

R.B. owns equity in Ampressa Therapeutics. G.G. receives research funds from IBM and Pharmacyclics and is an inventor on patent applications related to MuTect, ABSOLUTE, MutSig, MSMuTect and POLYSOLVER. I.L. is a consultant for PACT Pharma. B.J.R. is a consultant at and has ownership interest (including stock and patents) in Medley Genomics. All other authors declare no competing interests.

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Extended data figures and tables

Extended data fig. 1 summary of all results obtained for colorectal adenocarcinoma ( n  = 60) as an example..

a , Clustered heat maps of mutational timing estimates for gained segments, per patient. Colours as indicated in main text: green represents early clonal events, purple represents late clonal. b , Relative ordering of copy number events and driver mutations across all samples. c , Distribution of mutations across early clonal, late clonal and subclonal stages, for the most common driver genes. A maximum of 10 driver genes are shown. d , Clustered mutational signature fold changes between early clonal and late clonal stages, per patient. Green and purple indicate, respectively, a signature decrease and increase in late clonal from early clonal mutations. Inactive signatures are coloured white. e , As in d but for clonal versus subclonal stages. Blue indicates a signature decrease and red an increase in subclonal from clonal mutations. f , Typical timeline of tumour development. Similar result summaries for all other cancer types can be found in the  Supplementary Information (pages 46–77).

Extended Data Fig. 2 Comparison of methods used for timing of individual copy number gains.

a , b , Pairwise comparison of the three approaches for timing individual copy number gains. c , Comparison using simulated data, showing high concordance.

Extended Data Fig. 3 Early copy number gains in brain cancers.

a , Three illustrative examples of glioblastoma with trisomy 7. The red arrow depicts the expected VAF cluster of point mutations preceding trisomy 7, which usually contains less than three SNVs. b , Distributions of the number of SNVs preceding trisomy 7 and total number of mutations on chromosome (chr) 7 in n  = 34 GBM samples with trisomy 7. c , Medulloblastoma example with isochromosome 17q. d , Distributions of SNVs on 17q in n  = 95 samples with isochromosome 17q; 74 out of 95 samples have less than 1 SNV preceding the isochromosome.

Extended Data Fig. 4 Validation of relative ordering model reconstruction based on simulated cohorts of whole-genome samples.

a , Relative ordering model (PhylogicNDT LeagueModel) results for a simulated cohort of samples ( n  = 100) from a single generalized relative order of events (with varied prevalence) showing high concordance with the true trajectory. Probability distributions show the uncertainty of timing for specific events in the cohort. b , Relative ordering model results on a simulated cohort of samples ( n  = 95) from a complex mixture of trajectories with different order of events showing high concordance with the expected average trajectory. c , Estimation of accuracy of the relative ordering model reconstruction by simulation of a set of 100 cohorts ( n (samples) = 100) with random trajectory mixtures and quantifying the distance in log odds early/late from perfect ordering. For the vast majority of events (even with low number of occurrences in the cohort), the log odds error does not exceed 1, confirming that very few events would switch between timing categories. The inset box corresponds to the first and third quartiles of the distribution, the horizontal line indicates the median and whiskers include data within 1.5× the IQR from the box. d , Simulated data show concordant timing in cohorts with WGD ( n  = 245). Exclusion of samples with WGD (right, n  = 242) introduces only a mild drop in accuracy, indicating that WGD is beneficial but not necessary for the reconstruction. Red dot = true rank. e , Estimated log odds in observed data including WGD (left, n  = 245) and without (right, n  = 242), across different mutation types. The inset box corresponds to the first and third quartiles of the distribution, the horizontal line indicates the median and whiskers include data within 1.5× the IQR from the box.

Extended Data Fig. 5 Correlation between the league model and Bradley–Terry model ordering.

Direct comparison for each tumour type of the league and Bradley–Terry models for determining the order of recurrent somatic mutations and copy number events. Axes indicate the ordered events observed in the respective tumour types. Correlation is quantified by Spearman’s rank correlation coefficient. A total of n  = 756 ordered events are shown.

Extended Data Fig. 6 Examples of mutation spectrum changes across tumour evolution.

a , Three examples of tumours with substantial changes between mutation spectra of early (top) and late (bottom) clonal time points. b , Three examples of tumours with substantial changes between mutation spectra of clonal (top) and subclonal (bottom) time points.

Extended Data Fig. 7 Overview of early-to-late clonal and clonal-to-subclonal signature changes across tumour types.

a , b , Pie charts representing signature changes per cancer type for early-to-late clonal signature changes ( a ) and clonal-to-subclonal signature changes ( b ). Signatures that decrease between early and late are coloured green; signatures that increase are purple. The size of each pie chart represents the frequency of each signature. Signatures are split into three categories: (1) clock-like, comprising the putative clock signatures 1 and 5; (2) frequent, which are signatures present in ten or more cancer types; and (3) cancer-type specific, which are in fewer than ten cancer types and are often limited to specific cohorts.

Extended Data Fig. 8 Age-dependent mutation burden and relapse samples indicate near-normal CpG>TpG mutation rate in cancer, with moderate acceleration during carcinogenesis.

a , Across all cancer samples, a predominantly linear accumulation of CpG>TpG mutations (scaled to copy number) is observed over time, as measured by the age at diagnosis. b , Cancer-specific analysis of the CpG>TpG mutation burden as a function of age at diagnosis for n  = 1,978 samples of 34 informative cancer types. The dotted line denotes the median mutations per year (that is, not offset), and shading denotes the 95% credible interval of a hierarchical Bayesian linear regression model across all data points. Slope and intercepts are drawn for each cancer type from a gamma distribution, respectively; inference was done by Hamiltonian Monte Carlo sampling. c , Maximum a posteriori estimates of rate and offset for 34 cancer types with 95% credible intervals as defined in b . d , Mutation rate inferred from cancer as in b and from selected normal tissue sequencing studies of n  = 140 normal haematopoietic stem cells, n  = 1 normal skin sample, n  = 182 samples from normal endometrium, and n  = 445 normal colonic crypts; error bars denote the 95% confidence interval. e , Median fraction of mutations attributed to linear age-dependent accumulation, based on estimates from b and the age at diagnosis for each sample. Error bars denote the 95% credible interval. f , g , CpG>TpG mutations per gigabase for ovarian cancer ( f ) and breast cancer ( g ) samples with matched primary and relapse samples. h , Increase in CpG>TpG mutation rate inferred from paired primary and relapse samples for six cancer types. Bars denote the range of the rate increase for different scenarios of copy number evolution, assuming ploidy changes have occurred prior (upper value) or posterior (lower value) to the branching between primary and relapse sample.

Extended Data Fig. 9 Real-time estimates indicate long latencies for some samples caused by the absence of early mutations.

a , Time of WGD for n  = 571 individual patients, split by tumour type with an estimated mutation rate increase of 5×, except for ovary–adenocarcinoma (7.5×) and CNS (2.5×). Error bars represent 80% confidence intervals, reflecting uncertainty stemming from the number of mutations per segment and onset of the rate increase. Box plots demarcate the quartiles and median of the distribution with whiskers indicating 5% and 95% quantiles. b , Scatter plots showing the time of diagnosis ( x axis) and inferred time of WGD ( y axis) with error bars as in a . c , Scatter plot of early (co-amplified) CpG>TpG mutations ( y axis) as a function of the mutational time estimate of WGD ( x axis). The black line denotes a nonlinear loess fit with 95% confidence interval. Colours define the cancer type as in a . d , Total CpG>TpG mutations ( y axis) as a function of the mutation time estimate of WGD ( x axis). Colours and fit as in c . Early molecular timing is thus caused by a depletion of early CpG>TpG mutations, rather than an inflation of late CpG>TpG mutations. e , Estimated median WGD latency of n  = 571 patients as in a for fixed ( x axis) versus patient specific rate increases, depending on the observed CpG>TpG mutation burden, allowing for a higher (up to 10×) mutation rate increase in samples with more mutations ( y axis). Error bars denote the IQR. f , Timing of subclonal diversification using CpG>TpG mutations in n  = 1,953 individual patients. Box plots and error bars for data points as in a . g , Comparison of the median duration of subclonal diversification per cancer type assuming branching and linear phylogenies.

Supplementary information

Supplementary information.

This file contains a more detailed description of all methods, three supplementary notes, and summary pages for each PCAWG cohort, with sample-level figures representing the results of each of the life history analyses: timing of gains, ordering of events, timing of drivers, signature changes and evolutionary timelines.

Reporting Summary

PCAWG Consortium author list: This file contains a full list of consortium members.

Source Data Fig. 1

Source data fig. 2, source data fig. 3, source data fig. 4, source data fig. 5, source data fig. 6, source data extended data fig. 3, source data extended data fig. 5, source data extended data fig. 6, source data extended data fig. 8, source data extended data fig. 9, rights and permissions.

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Gerstung, M., Jolly, C., Leshchiner, I. et al. The evolutionary history of 2,658 cancers. Nature 578 , 122–128 (2020). https://doi.org/10.1038/s41586-019-1907-7

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• Sunlight exposure is linked to skin cancer. The first epidemiologic study of sunlight and skin cancer was reported; earlier observations had linked chronic skin conditions common in sailors to exposure to the radiation effects of the sun. Later work in animal models confirmed that skin cancer could be induced by ultraviolet light and sunlight. (1)(2)(3)
• American Association for Cancer Research is founded by four surgeons, five pathologists, and two biochemists ( right ) on May 7 in Washington, DC.
• Japanese cancer journal, Gann: Japanese Journal of Cancer Research (now titled Cancer Science ), is first published.
• Nine research papers are presented at the first Annual Meeting of the AACR in New York City.

• Cell-free extracts transmit cancer from one animal to another. Cell-free agents were shown to transmit leukosis, a form of leukemia and lymphoma, and sarcomas in chickens. This finding would later be verified as evidence for viral initiation of cancer. (4)(5)

• Martha Tracy ( right ), from Women’s Medical College in Philadelphia (later dean of that college), becomes the AACR’s first female member.
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• Procedures for in vitro tissue culture are developed. The fundamental culture techniques, now ubiquitous in the laboratory, allowed researchers to study the evolution of tumor tissue under known conditions and to observe living cancer cells at every stage of growth. (6)
• French journal, Bulletin de l’Association Française pour l’Étude du Cancer , and the Italian journal, Tumori , are first published.

• AACR member Thomas S. Cullen, MD, presents “Education of the People as to What Can Be Done in Early Cases of Cancer” at the Annual Meeting. This appeal for public education led the Ladies’ Home Journal to publish “What Can We Do About Cancer,” the first consumer-oriented article about cancer.
• A group of volunteers—including AACR founding member and past president James Ewing—establishes the American Society for the Control of Cancer ( right ), precursor to the American Cancer Society.

• Alterations in chromosomes are postulated to cause tumor growth. From earlier work on sea urchin eggs and association of inappropriate segregation of chromosomes and changes in cell growth characteristics came the hypothesis that cancer was caused by abnormal chromosomes. (7)

• First experimental animal model of chemically induced cancer is developed. Repeated tarring of rabbit skin caused tumors. The discovery added to early evidence for the theory of chemical carcinogenesis, building upon the observation in 1775 of scrotal cancer in chimney sweeps. Later work published in the AACR’s The Journal of Cancer Research would isolate and identify the specific components of coal tar responsible. (8)(9)

• AACR begins publishing The Journal of Cancer Research , the first English language cancer journal.
• Oophorectomy decreases breast cancer in mice. Removal of the ovaries from female mice of a strain with a high incidence of spontaneous breast cancer resulted in a decrease in tumors. Later work published in The Journal of Cancer Research involving transplantation of ovaries into male mice showed an induction of mammary tumors, supporting the suggestion that hormones from the ovary could promote breast tumors. (10)(11)
• American Society for the Control of Cancer creates the first National Cancer Week as an extensive public education campaign.

• U.S. Public Health Service opens Office of Cancer Investigations at Harvard Medical School.
• Metabolic studies show that tumors exhibit anaerobic respiration. Whereas normal tissues use oxygen to break down nutrients for growth as their primary mode of respiration, it was observed that within tumors, cells respire anaerobically, fermenting sugars without oxygen. It will take several decades before hypoxia is revisited as a marker for tumors. (12)(13)
• Cancer is named one of the top three causes of death in America by U.S. Census Bureau.
• Genetic mutation is proposed as the origin of cancer. As an alternative to the infection theory of cancer, popular at the time because of the expansion of microbiology as a field of study, came the proposal that somatic mutation was the cause of cancer. As Mendel’s works were rediscovered in 1928, the field of genetics grew. The term “somatic mutation” had been coined in 1916. (14)(15)
• Cervical cancer cells are visible in smears of exfoliated vaginal cells. Findings of cervical cancer cells in smears were met with skepticism, and it would take until the 1960s before the “Pap” smear would become widely accepted as an effective method of screening and cancer prevention. (16)(17)

• X-rays are shown to be mutagenic. X-rays were shown to be mutagenic in the common fruit fly. This discovery formed the basis for thinking about how carcinogens participate in tumorigenesis. (18)

• First pure carcinogen, benzopyrene, is isolated from coal tar. The known cancer-causing environmental substance, coal tar, was fractionated into components and assayed in mouse models to identify the individual chemicals responsible for carcinogenesis. (19)
• Ransdell Act establishes the National Institute of Health.

• The American Journal of Cancer replaces The Journal of Cancer Research as the official AACR publication.

• Injected synthetic hormones induce breast cancer in mice. Building on work on endogenous hormones, it was demonstrated that addition of synthetic exogenous hormones such as folliculin (and in 1952, diethylstilbestrol) can induce cancer. (20)(21)
• Electron microscope is invented. The electron microscope permitted the visualization of minute subcellular structures, allowing observation of detailed differences between malignant and normal tissues. (22)

• National Cancer Institute Act establishes the National Cancer Institute (NCI) as an independent research institution.
• Transplantation of a single leukemic cell transmits leukemia in mice. Studies published in AACR’s The American Journal of Cancer showed that not all cancer cells behaved in an identical manner; some were uniquely capable of initiating and maintaining a tumor. This work laid the foundation for the later search for a cancer stem cell. (23)

• Telomeres are identified. The ends of chromosomes were shown to be protected by a structure that prevented their fusion. Later, it was shown that telomeres are repeated simple sequence elements that are added by an enzyme, telomerase, which is not normally expressed in somatic cells. In each cell division, telomeres shorten. When they become sufficiently truncated they cause the cells to enter into senescence and die, limiting the number of divisions a cell can undergo and suppressing tumor development. (24)(25)(26)

• Discovery of antigens explains why tumors can be transplanted within inbred strains. Previous work to transplant tumors had been successful in some instances but failed in others. The discovery of major histocompatibility antigens later led to an immunologic explanation that applied to grafts of normal tissue as well as to malignant tissue. (27)(28)
• Chemicals induce cancer in two distinct steps of initiation and promotion. Tumorigenesis was identified as a multistage disease, and it was shown that chemicals induce cancer in two distinct steps of initiation and promotion. A nonspecific irritant (wounding) was shown to promote tumorigenesis after initiation with a suboptimal dose of carcinogen (tarring or application of Shope papillomavirus to rabbit ears). Further study of the significance of cocarcinogenic action was later published in Cancer Research . (29)(30)
• Transplanted animal tumors are shown to grow blood vessels. Tumors transplanted into the ears of rabbits elicited a vascular network. This was early evidence of the phenomenon of angiogenesis, or new blood vessel growth, which would later become a target for antiangiogenesis cancer therapies. (31)

• Caloric restriction reduces tumors in mice. Studies published in The American Journal of Cancer and later in Cancer Research showed that caloric intake was proportional to the incidence of tumors of several kinds, including spontaneous mammary carcinomas and hepatomas in susceptible mouse strains and benzopyrene-induced skin tumors. Only recently, with the increasing prevalence of obesity in the global population, have the implications of the work been revisited. (32,33)

• Cancer Research replaces The American Journal of Cancer as AACR’s official journal.

• Hormone dependence of prostate cancer is demonstrated. In a study published in Cancer Research , the therapeutic use of physical castration or chemical castration by treatment with estrogens was shown to decrease disease burden in metastatic prostate cancer whereas injection of androgens increased metastases. (34)

• DNA is identified as the active material in the genes of bacteria. It was not known whether the protein or DNA components of the chromosomes contained the information necessary for inheritance. This work showed that DNA contained the heritable information and set the stage for many important works and techniques. (35)
• American Society for the Control of Cancer becomes the American Cancer Society.
• Public Health Services Act designates NCI as a division of the National Institutes of Health (NIH).
• Atomic Bomb Casualty Commission is established to monitor the effects of radiation exposure.

• Nitrogen mustard is established as the first chemotherapeutic agent. Observational reports that soldiers exposed to nitrogen mustard during wartime had low white blood cell counts led to testing of nitrogen mustard as chemotherapy for cancer. Intravenous nitrogen mustard was shown to slow the growth of lymphomas and leukemias in patients refractory to radiation therapy, and it achieved remissions of a few months. Nitrogen mustard was approved for cancer treatment in 1949. (36)
• Nuremberg Code establishes the legal principle of voluntary consent for human subjects of research.
• At the 38th AACR Annual Meeting, May 16-17, a policy presentation titled, “On the Organization and Support of Cancer Research,” concludes that the AACR should advocate for increased funding for cancer research.

• First successful chemotherapy for childhood leukemia is reported. A synthetic folate antagonist achieved a three-month remission in 10 of 16 children with leukemia. Although not successful by today’s standards, this was an important result that would lead to further work on antimetabolites and the first generation of effective chemotherapeutic agents. (37)
• United Nations establishes the World Health Organization.

• First rationally conceived nucleotide analog chemotherapeutic agents are developed. Drug design had been primarily by trial and error. The design of molecules similar to the bases of DNA, but sufficiently different to prevent replication, proved an effective drug targeting approach that led to several chemotherapeutic drugs for cancer such as 6-mercaptopurine and 5-fluorouracil, which are still in use today. (38,39)

• Epidemiologic work links tobacco smoking to lung cancer. A retrospective analysis of the smoking habits of patients with lung cancer showed an association with tobacco. This was followed by a prospective study of male doctors that showed a clear relationship between smoking and lung cancer deaths. Tobacco exposure is now a known risk factor for many cancer types, accounting for an estimated 30% of all cancer mortality. (40-42)
• Leukemia in mice is shown to be transmissible by a virus. Leukemia had been considered an inherited disease before it was shown that it could be transmitted from one mouse strain to another by a virus and then passed from one generation to another via vertical transmission. These findings laid the groundwork for later research on other mouse tumor viruses and those in other species. (43)
• Cobalt-60 irradiator is developed. Radiotherapy previously had been carried out using radium, which was in limited supply and needed to be used in close proximity to the tumor. Radioactive cobalt provided a continuous source with greater ability to treat internal tumors, with less damage to the intervening tissue. Clinical cobalt-60 is still used in much of the developing world. (44)

• Ultrasound imaging is developed for detecting tumors. Although earlier studies had used ultrasound as a therapy and had examined its use as an imaging tool, research showed that ultrasound could detect differences in density between malignant and normal tissues. (45)

• AACR Annual Meeting abstracts are published for the first time as Proceedings of the American Association for Cancer Research (154 abstracts).
• Structure of DNA is described. Not only was the global structure of DNA identified, but how the bases pair and possible implications for methods of replication were also elucidated. (46)
• Human carcinoma cell line, HeLa, is established from the cells of Ms. Henrietta Lacks. The HeLa epithelial cell line is readily grown in laboratories worldwide and has become a fundamental tool for studying many aspects of molecular biology. Stable cell lines such as HeLa allow researchers to use genetically identical cells for experiments over long-term courses of repeated culturing in a manner not possible with primary cells. (47)

• Medical linear accelerator is developed for radiotherapy. Unlike early radiotherapy machines that used a radioactive source to generate X-rays, the linear accelerator produces a beam of electrons. This eliminated the need to replace the radioactive source and is limited in power by the length of the accelerator tube. (48)

• Tumor clonogenic assay is developed. Although human cells had been cultured before, these new methods allowed cultures to be propagated from single human cells, enabling the kind of detailed genetic studies previously only possible for bacterial cells. (49)
• U.S. Congress funds National Chemotherapy Program to test compounds that might be effective against cancer.

• First successful chemotherapy for solid tumors is reported. Building on earlier work on folate and aminopterin, another antifolate, methotrexate, was developed.The drug was shown to be effective in a small group of three patients with metastatic choriocarcinoma and chorioadenoma. (50)

• Elizabeth C. Miller ( right ) is the first woman elected to the AACR Board of Directors.
• Association of American Cancer Institutes (AACI) is founded. Its mission is to reduce the burden of cancer by enhancing the impact of North America’s leading academic cancer centers.
• Food Additives Amendment prohibits food additives shown to induce cancer in humans or animals.

• AACR membership passes 1,000.
• In vitro viral carcinogenesis is demonstrated. Earlier work had shown that viruses could be used to transmit cancer from one organism to another. New studies showed that chick embryo cells infected with Rous sarcoma virus continued to grow in culture and produce more virus. The infected cells had changes in morphology and rapid, disordered growth characteristic of cancer cells. (51)

• DNA repair after radiation is demonstrated. Chinese hamster ovary cells subjected to X-irradiation and surviving did not display heritable damage but repaired the damage prior to cell division. This finding confirmed the presence of DNA repair mechanisms, later shown to be defective in some cancers. (52)
• Dose-response relationship is shown in radiation-induced leukemia. Radiation carcinogenesis was unequivocally established in human populations, and the nature of the dose-response relationship was described. (53)
• Radioimmunoassay is developed. The radioimmunoassay uses antibodies to detect the amounts of specific proteins in a solution. Originally developed to measure insulin levels in the blood of diabetics, this technique is now the basis for diagnostic tests to measure serum proteins and biomarkers, such as prostate-specific antigen, although now the detection mechanism often uses fluorescent rather than radioactive labeling. (54)
• American Cancer Society urges widespread use of Pap smear to detect cervical and uterine cancers.
• Philadelphia chromosome is discovered . An abnormally small chromosome was identified in the neoplastic cells of patients with chronic myelogenous leukemia. This small chromosome, later named the Philadelphia chromosome after the city in which it was discovered, was the first chromosomal abnormality found to be consistently associated with a specific human neoplasm. (55)
• Growth factors are purified and identified. The fact that growth factors were necessary for cells to survive and replicate had long been known, but the individual components of serum responsible had not been identified. The purification of nerve-growth factor led to the identification of other growth factors, their cognate receptors, and their complex signaling pathways. These pathways have emerged as novel targets for therapies such as those targeting the epidermal growth factor receptor (EGFR). (56)

• Screening techniques for prevention of colon cancer are adopted. The sigmoidoscope permitted early identification of colorectal cancer as well as precancerous polyps, leading to increased survival rates. It is estimated that screening by sigmoidoscopy, colonoscopy, barium enema, or fecal occult blood testing may result in a 20% decrease in colorectal cancer mortality. (57,58)
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Cancer patients can now be 'matched' to best treatment with DNA and lab-dish experiments

Identifying the most effective cancer treatment for a given patient from the get-go can help improve outcomes.

Despite many efforts to find better, more effective ways to treat cancer, it remains a  leading cause of death by disease  among children in the U.S.

Cancer patients are also getting younger. Cancer diagnoses among those under 50 has risen by  about 80% worldwide  over the past 30 years. As of 2023, cancer is the  second-leading cause of death  both in the U.S. and around the world. While death rates from cancer have decreased over the past few decades,  about 1 in 3 patients in the U.S.  and  1 in 2 patients worldwide  still die from cancer.

Despite advances in standard cancer treatments, many cancer patients still face uncertain outcomes when these treatments prove ineffective. Depending on the stage and location of the cancer and the patient's medical history, most cancer types are treated with a mix of radiation, surgery and drugs. But if those standard treatments fail, patients and doctors enter a trial-and-error maze where effective treatments become difficult to predict because of limited information on the patient's cancer.

My mission as a  cancer researcher  is to build a personalized guide of the most effective drugs for every cancer patient. My team and I do this by testing different medications on a patient's own cancer cells before administering treatment, tailoring therapies that are most likely to selectively kill tumors while minimizing toxic effects.

In our newly published results of the first clinical trial combining drug sensitivity testing with DNA testing to identify effective treatments in children with cancer, an approach called  functional precision medicine , we found this approach  can help match patients  with more FDA-approved treatment options and significantly improve outcomes.

What is functional precision medicine?

Even though two people with the same cancer might get the same medicine, they can have very different outcomes. Because each patient's tumor is unique, it can be challenging to know which treatment works best.

To solve this problem, doctors analyze DNA mutations in the patient's tumor, blood or saliva to match cancer medicines to patients. This approach is called  precision medicine . However, the relationship between cancer DNA and how effective medicines will be against them is very complex. Matching medications to patients based on a single mutation overlooks other genetic and nongenetic mechanisms that influence how cells respond to drugs.

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How to best match medicines to patients through DNA is still a major challenge. Overall,  only 10% of cancer patients   experience a clinical benefit  from treatments matched to tumor DNA mutations.

Functional precision medicine takes a different approach to personalizing treatments. My team and I take a sample of a patient's cancer cells from a biopsy, grow the cells in the lab and expose them to over 100 drugs approved by the Food and Drug Administration. In this process, called  drug sensitivity testing , we look for the medications that kill the cancer cells.

New clinical trial results

Providing functional precision medicine to cancer patients  in real life  is very challenging. Off-label use of drugs and financial restrictions are key barriers. The health of cancer patients can also deteriorate rapidly, and physicians may be hesitant to try new methods.

But this is starting to change. Two teams in Europe recently showed that functional precision medicine could match effective treatments to  about 55% of   adult patients  with blood cancers such as leukemia and lymphoma that did not respond to standard treatments.

Most recently, my team's clinical trial  focused on childhood cancer patients  whose cancer came back or didn't respond to treatment. We applied our functional precision medicine approach to 25 patients with different types of cancer.

Our trial showed that we could provide treatment options for almost all patients in less than two weeks. My colleague  Arlet Maria Acanda de la Rocha  was instrumental in helping return drug sensitivity data to patients as fast as possible. We were able to provide test results within 10 days of receiving a sample, compared with the roughly 30 days that standard genomic testing results that focus on identifying specific cancer mutations typically take to process.

Most importantly, our study showed that  83% of cancer patients  who received treatments guided by our approach had clinical benefit, including improved response and survival.

Expanding into the real world

Functional precision medicine opens new paths to understanding how cancer drugs can be better matched to patients. Although doctors can read any patient's DNA today, interpreting the results to understand how a patient will respond to cancer treatment is much more challenging. Combining drug sensitivity testing with DNA analysis can help personalize cancer treatments for each patient.

I, along with colleague  Noah E. Berlow , have started to add artificial intelligence to our functional precision medicine program. AI enables us to analyze each patient's data to better match them with tailored treatments and drug combinations. AI also allows us to understand the complex relationships between DNA mutations within tumors and how different treatments will affect them.

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My team and I have  started two   clinical trials  to expand the results of our previous studies on providing treatment recommendations through functional precision medicine. We're recruiting a larger cohort of adults and children with cancers that have come back or are resistant to treatment.

The more data we have, the easier it will become to understand how to best treat cancer and ultimately help more patients access personalized cancer treatments.

This edited article is republished from The Conversation under a Creative Commons license. Read the original article .

Diana Azzam is an Assistant Professor and Research Director of the newly established Center for Advancing Personalized Cancer Treatments (CAPCT) at Florida International University. She has a Masters in Biochemistry from the American University of Beirut, Lebanon and a PhD in Biochemistry & Molecular Biology from the University of Miami, Florida. Her lab focuses on implementing functional precision medicine (FPM) approaches in adult and pediatric cancer patients that have run out of treatment options. Working with local hospitals including Nicklaus Children's Hospital and Cleveland Clinic Florida, her lab delivers individualized treatment plans based on a patient's cancer genomic profile and ex vivo drug response. She is currently engaged in two clinical studies to assess feasibility and clinical utility of FPM in relapsed/refractory patients with childhood cancer (ClinicalTrials.gov registration: NCT05857969) and adult cancer (ClinicalTrials.gov registration: NCT06024603). She is working on setting up the first CLIA-certified lab in the State of Florida dedicated for functional cancer drug testing. Her goal is to launch large-scale prospective multi-center randomized clinical trials to better assess efficacy of FPM approaches in the treatment of refractory/relapsed cancers. In parallel, she is working on utilizing FPM as a tool to reduce health disparities in childhood cancer patients from minority populations. She is also integrating a novel machine learning approach to identify specific biomarkers among minority populations that can be targeted using FDA-approved drugs. Her lab also investigates cancer stem cells and how they may result from chronic environmental exposures to toxic metals such as arsenic.

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Terry Fox: A Hero's Journey of Hope and Determination Daily Sports History

Join us as we celebrate the extraordinary life and legacy of Terry Fox, a Canadian icon whose courageous Marathon of Hope inspired millions around the world. In this short episode, we delve into Fox's remarkable journey—a marathon across Canada to raise funds for cancer research, despite battling cancer himself.Discover the indomitable spirit of Terry Fox as he ran over 5,000 kilometers on his prosthetic leg, capturing the hearts of Canadians and people worldwide. Hear stories of perseverance, resilience, and the power of one person to make a difference in the fight against cancer.Through concise storytelling, we honor Terry Fox's enduring legacy as a beacon of hope, courage, and determination, inspiring generations to continue the fight against cancer and pursue their dreams against all odds. We are being featured on PODCAST GURU: https://app.podcastguru.io/podcast/daily-sports-history-1715849627 Website: dailysportshistory.com Email: [email protected] YouTube: YouTube.com/@dailysportshistory Twitter: twitter.com/dailysportshis Facebook: facebook.com/profile.php?id=61551687917253&mibextid=ZbWKwL Tiktok: tiktok.com/@daily.sports.history?_t=8hHPnNSCqfm&_r=1 #sports #sportshistory #sportspodcast #podcast #TerryFox #MarathonOfHope #CancerResearch #InspirationalFigures #CanadianHeroes #Activism #CancerAwareness #Humanitarianism

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A History of Cancer Research: Tumor Viruses

Early studies of transmissible tumors in chickens provided evidence that viruses such as avian leukosis virus (ALV) and Rous sarcoma virus (RSV) can cause cancer in these animals. Doubts about the relevance to human tumors and failures to replicate some early work meant the field of tumor virology followed a bumpy course. Nevertheless, viruses that can cause cancers in rodents and humans were ultimately identified, and several Nobel prizes were awarded for work in this area. In this excerpt from his forthcoming book on the history of cancer research, Joe Lipsick looks back at the early history of tumor virus research, from some of the early false starts and debates, to discovery of reverse transcriptase, and identification of human papilloma virus (HPV) as the major cause of cervical cancer.

HERE A CHICK, THERE A CHICK

The early twentieth century witnessed the rise and ignoble fall of Fibiger's Nobel Prize–winning “discovery” of worms as a cause of cancer. But all was not rotten in the state of Denmark. Elsewhere at the University of Copenhagen, Vilhelm Ellerman and Oluf Bang were also testing whether cancer might be an infectious disease. In 1908 they published a paper entitled “Experimental Leukemia in Chickens.” They had found that leukemia, a cancer of the blood cells, could be transmitted from one bird to another by injection ( Fig. 1 ). Furthermore, the causative agent was able to pass through filters too fine to permit passage of any cells, animal or bacterial. Such filterable agents, first discovered in plants, eventually became known as viruses. Ellermann and Bang had discovered avian leukosis virus (ALV), the first known tumor virus. For reasons that remain unclear, their work did not attract the attention it deserved. One criticism was that although one could transmit this leukemia by injection, there was no observable transmission from bird to bird in the absence of injection. Furthermore, not every injected animal developed the disease (∼40%), and those that did often took a while to do so (6–12 mo). There was also a concern that the increased number of white blood cells might be a physiological response to infection, rather than a true malignant proliferation. Finally, it was not then widely accepted that animals, particularly non-mammals, were good models for human disease.

Ellermann and Bang's drawings of normal chicken bone marrow ( left ) and leukemic chicken bone marrow ( right ). The normal marrow contains dense, dark trabeculae of bone. The cells in the spaces between trabeculae are nucleated erythrocytes (red blood cells). The leukemic marrow contains little bone, many immature leukocytes (white blood cells, later shown to be B lymphocytes), and very few erythrocytes. (Reprinted from Ellermann V, Bang O. 1909. Z Hygeine Infektionskrakheiten 63: 231–273.)

Two years after Ellermann and Bang had published their work, Peyton Rous at the Rockefeller Institute described a transmissible sarcoma in chickens ( Fig. 2 ). The original tumor “was found in a barred Plymouth Rock hen of light color and pure blood” that was brought to him by a chicken breeder. Rous minced the tumor into small pieces, injected part into the other breast of the same chicken and part into two other chickens of the same brood. The original chicken died of widespread cancer 35 d later. By this time, one of the other injected chickens had also developed a palpable tumor. In his initial report Rous noted, “The tumor is at best so difficult of propagation that no attempts have been made to determine whether it can be transmitted by cell-fragments, or by cell-free derivatives.”

The origins of Rous sarcoma virus. ( Top ) A sarcoma caused by injection of fragments of the transmissible tumor. ( Bottom ) Histopathologic evidence of a sarcoma invading into muscle. (Reprinted from Rous P. 1910. J Exp Med 12: 696–705.)

However, within a year Rous had found that by passage from chicken to chicken, the transmissible tumor had become increasingly aggressive and was now capable of metastasizing. By 1911 he was able to follow in the footsteps of Bang and Ellermann and transmit this cancer by a filterable agent. This virus eventually became known as Rous sarcoma virus (RSV). As before, the work was not generally accepted as proof that cancer could be caused by an infectious agent. On the contrary, physicians were spending considerable time and effort trying to disabuse the public of the view that human cancer was infectious. This mistaken belief often resulted in the shunning or even the quarantine of patients afflicted with cancer. In search of better career prospects, Rous stopped working on RSV a few short years after publishing his landmark paper in 1911.

Extracts of chicken tumors from Rous's laboratory did make it across the pond to England, only to become entangled in a rather Dickensian tale. It began with an unusual proposition made to a studious railway stationmaster named William Bullock. If Bullock would agree to take a wealthy but childless benefactor's name, he would be left a small fortune with which he could attend medical school. Thus, was he reborn as William Gye. He enrolled at Edinburgh University, pursued a career in cancer research, and eventually was able to repeat the experiments of Rous. Taking things one step further, he then found that he could amplify the infectious material in vitro using fragments of chicken embryos. He also claimed to have isolated similar infectious agents in tumors from mice, from rats, and from humans, all of which could cause tumors in chickens.

Gye then collaborated with J.E. Barnard, a wealthy hatter and amateur microscopist, to obtain what they believed were images of the infectious cancer virus particles. These studies were published in 1925 as back-to-back papers in The Lancet . Not surprisingly, this work attracted wide attention in the popular press, helping to again fuel fears about the infectious nature of human cancer. Ultimately, none of this work stood the test of time, except for Gye's replication of Rous's work on chicken viruses. Gye went on to become a very successful cancer research administrator, eventually serving as the Director of the Imperial Cancer Research Fund Laboratories at Mill Hill.

The field of tumor virology itself also followed a rather bumpy course. Although additional tumor viruses were isolated from chickens in Japan and elsewhere, critics harped on the lack of evidence for similar viruses in mammals. In 1933 Richard Shope at the Rockefeller Institute identified a virus capable of causing papillomas (warts) in rabbits. Rous himself propagated and studied this virus for many years. A few years later John Bittner discovered a transmissible mammary cancer in mice that was caused by a milk-borne virus that became known as mouse mammary tumor virus (MMTV). In the early 1950s, Ludwik Gross identified two more mouse tumor viruses, a murine leukemia virus and a polyoma virus, which caused many different types of cancer. Tumor viruses were then identified in a variety of other mammals, including rats, cats, cows, and monkeys.

An adenovirus isolated from human tissue was shown to cause cancer in rodents in 1962, but was ultimately found not to be a cause of human cancer. Simian vacuolating virus 40 (SV40), a contaminant discovered in cells used to produce polio vaccine, was also shown to cause cancer in rodents in 1962. However, there has been a lack of convincing evidence that SV40 causes human cancer, despite much effort.

Finally, in 1964 Michael Epstein and Yvonne Barr published evidence of the first human tumor virus. They had discovered a herpes-like virus in the lymphoblasts of patients with Burkitt's lymphoma, a cancer endemic in children in tropical Africa. Epstein–Barr virus was later shown to cause both mononucleosis (a benign proliferation of B lymphocytes) and a form of nasopharyngeal cancer endemic in certain regions of China. On the heels of the discovery of the first human tumor virus, Rous was finally awarded the Nobel Prize in Physiology or Medicine in 1966 for his discovery of a chicken sarcoma virus 55 years earlier.

THE HUMAN CONDITION

Rising political pressure in the 1970s caused President Richard Nixon to announce a “war on cancer.” Ironically, much of this pressure came from Mary Lasker, a champion of medical research whose husband Albert Lasker had created advertising campaigns that greatly increased the popularity of cigarettes ( Fig. 3 ). Viruses turned out to be important causes of cancer in domesticated animals, such as chickens, laboratory mice, house cats, and cattle. However, despite the expenditure of much effort and many dollars, viruses were not found to cause the majority of human cancers. There were a number of highly publicized false leads, derisively referred to as “rumor viruses.” These reports were most often a result of contamination of human cells by animal viruses in the laboratory. The Special Virus Cancer Program, a directed medical research effort within the National Cancer Institute (NCI), had been charged with the discovery of new human cancer viruses. The program began in 1964, grew to consume substantial resources, and was eventually discontinued in the late 1970s. In part this was due to criticism from scientists outside the walls of the NCI, who favored peer-reviewed research directed by independent individual investigators rather than a centralized bureaucracy that managed large research contracts.

The Laskers’ contributions to cancer dissemination ( top ) and to political pressure for increasing spending on research for a cancer cure ( bottom , advertisement in The Washington Post ). ( Top , From the collection of Stanford Research Into the Impact of Tobacco Advertising [tobacco.stanford.edu]; bottom , https://profiles.nlm.nih.gov/spotlight/tl/catalog/nlm:nlmuid-101584665X20-doc .)

Eventually other human tumor viruses were discovered. Most of these viruses cause relatively rare types of cancer (e.g., HTLV-I causes lymphoid cancers of the skin; HTLV-II causes a rare form of leukemia; HHV-8 causes Kaposi's sarcoma; MCV causes Merkel cell cancer). One notable exception is a family of human papilloma viruses (HPVs) very similar to those discovered in rabbits by Shope. Two such viruses (HPV16 and HPV18) were shown by Harald zur Hausen in the 1980s to be the major cause of cancer of the uterine cervix in women. HPV also causes head and neck cancers and anogenital cancers. These observations led to a Nobel Prize in Physiology or Medicine for zur Hausen in 2008, and to the creation of preventive HPV vaccines, the first of which was approved by the FDA for clinical use in 2006.

In addition to viruses that appear to directly cause human cancer, certain viruses and other infectious agents appear to cause cancer in part via the response of the host to infection. For example, infection with hepatitis B and C viruses is strongly associated with cancer of the liver, infection with Helicobacter pylori bacteria is strongly associated with cancer of the stomach, and infection with Schistosoma haematobium is strongly associated with bladder cancer in some countries. Hepatitis B virus and H. pylori have been shown to encode proteins that can promote cell proliferation. However, these cancers all appear to require repeated cycles of infection, chronic inflammation, and tissue repair, resulting in the continued proliferation of cells that have also been exposed to environmental carcinogens. The result is an unholy alliance of three old rivals—the irritation theory, the germ theory, and the mutagen theory of cancer.

THE RISE OF THE QUANTS

In the mid-twentieth century, a number of physicists turned their attention from physics to biology. A particularly influential book called What Is Life? by Erwin Schrödinger proposed that genetic information might be contained within a chemical form. This idea spurred a group of physicists-turned-biologists to focus their attention on simpler and simpler genetic systems that could be studied by quantitative methods. The result was the Phage Group led by Max Delbrück, Alfred Hershey, and Salvador Luria. By studying the viruses of bacteria (bacteriophage or phage), they and their colleagues were able to deduce many of the basic principles of molecular biology. A by-product of their efforts was the development of methods for quantitative virology, largely based on the plaque assay first described by Félix d'Hérelle in 1917.

Similar advances in animal virology required the development of methods for studying viruses in systems simpler than a whole animal. In the early twentieth century, Alexis Carrel, a Nobel Prize–winning French surgeon, developed and publicized rather complex and somewhat mystical methods for culturing fragments of tissue in the laboratory. In 1928 Carrel reported that he could use these cultures to propagate RSV. He also claimed to have kept a continuous culture of embryonic chicken heart cells alive for decades in his laboratory at the Rockefeller Institute. His work attracted the attention of Charles “Lucky Lindy” Lindbergh, who with Carrel sought a path to physical immortality ( Fig. 4 ). Eventually Carrel's immortal chicken heart experiments failed to be repeated by others. Most likely, new cells had been continually added via the embryo extracts used to “feed” the cultures. Carrel later returned to Europe, where he became an advocate of eugenics for the Vichy government in Nazi-occupied France, thus sharing sympathies with Lindbergh.

Charles Lindbergh, Alexis Carrel, and the quest for immortality. (Image from the National Portrait Gallery.)

The fields of animal cell culture and animal virology progressed slowly until the 1940s, when recurrent polio epidemics spurred intense interest in animal (including human) virology. In 1948, John Enders and his colleagues succeeded in propagating poliovirus in cultures of human embryonic tissue fragments. Their work led to the intensely competitive development of polio vaccines by Jonas Salk and Albert Sabin. Based on the work of Enders, in 1954 Renato Delbecco and Marguerite Vogt developed a plaque assay for poliovirus that was similar to the method used to study the viruses that had lysed bacteria. At the same time, Harry Eagle at the National Institutes of Health (NIH) was systematically determining the requirements for animal cell growth. The result was a defined medium that, when supplemented with relatively small amounts of animal serum, permitted the reproducible growth of animal cells in culture without the need for embryo extracts or plasma clots. Together these powerful methods were then applied to the quantitative study and isolation of mutants of an ever-increasing number of animal viruses, including other important human pathogens like influenza.

But what about tumor viruses? How could one study viruses that caused cells to proliferate rather than die? The key insight came from Howard Temin and Harry Rubin, a graduate student and a postdoctoral fellow working in Dulbecco's laboratory. They infected dishes of adherent fibroblasts from chicken embryos with different dilutions of RSV, layered agar over the cultures, and then watched and waited. Following infection with very dilute stocks of virus, distinct patches of transformed cells appeared ( Fig. 5 ). Normal fibroblasts are flat, spindly cells that stop proliferating once they touch one another (contact inhibition). By contrast, RSV-transformed fibroblasts round up and keep proliferating, eventually forming small mounds of cells (transformed foci) that are very refractile when seen through a phase-contrast microscope. The agar overlay was an important modification of the method described two years earlier by Manaker and Groupé, because it greatly decreased secondary foci caused by subsequent rounds of infection or by detachment and diffusion of transformed cells. Once again using the logic of the Phage School, Temin and Rubin were able to rapidly and readily quantitate stocks of a tumor virus in a far easier fashion than had been possible with assays in whole animals or chicken eggs. Temin and Rubin observed a linear relationship between the concentration of the virus and the number of foci that extended over a thousandfold range. These results implied that infection with a single viral particle was sufficient to cause the oncogenic transformation of a normal cell. Therefore, by isolating virus from a single focus formed at a low concentration of virus, one could isolate a biological clone that had arisen from a single virus particle.

Temin and Rubin's focus assay for morphologic transformation by Rous sarcoma virus. ( Left ) Experimental scheme. ( Center ) A transformed focus visualized by phase contrast microscopy. ( Right ) Relationship between viral concentration and number of foci. ( Center and right panels from Temin H, Rubin H. 1958. Virology 6: 669–688, with permission from Elsevier.)

PROVIRAL HERESY

Temin continued these studies in his own laboratory. He noticed that some isolates of RSV transformed cells with a cobblestone-like morphology (round), whereas other isolates of RSV transformed cells with a spindly morphology (fusiform) ( Fig. 6 ). Remarkably, these characteristics bred true. Cells transformed by a “round” variant of RSV and the progeny of these cells remained “round,” as did naive cells transformed by viruses isolated from “round” cells. Similarly, cells transformed by the “fusiform” variant of RSV and the progeny of those cells remained “fusiform,” as did naive cells transformed by viruses isolated from “fusiform” cells. Furthermore, the conversion of one viral variant into another occurred very rarely, if ever. These observations led Temin to propose that the transformed state was a stably inherited property of the infected cells. To account for this heritable state, he further proposed that the genetic material of the virus somehow became part of the genetic material of the cell.

Cells transformed by fusiform (f) variant and round (r) morphological variants of Rous sarcoma virus. (Photomicrograph by Peter Vogt from Coffin J, et al. 1997. Retroviruses . Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, with permission from Peter Vogt.)

There were precedents for viral integration into the host genome in the world of bacteriophage biology. In the 1920s, Eugene and Elizabeth Wollman at the Institut Pasteur in Paris had discovered a latent form of bacteriophage that did not cause cells to lyse. Sadly, the Wollmans were deported from France and perished in Auschwitz. After the end of World War II, their former colleague Andre Lwoff continued their work. By 1949 he had shown that some bacteriophage could exist stably within bacteria in a nonlytic (lysogenic) state. This latent form of the virus (prophage) could be inherited during bacterial division and later be re-activated to produce virus in the absence of any additional infection. Careful studies eventually showed that lysogenic bacteriophage DNA becomes integrated into the genomic DNA of infected bacteria. Much of this latter work was done by François Jacob and by Elie Wollman, the surviving son of Eugene and Elizabeth.

Temin was reportedly unaware of this work because Delbrück (with whom Elie Wollman had trained) and his colleagues at Caltech did not believe in lysogeny. However, by 1962 Vogt and Dulbecco had provided evidence via nucleic acid hybridization that polyoma, a lytic DNA tumor virus originally discovered in mice, was retained in a nonlytic form in oncogenically transformed hamster cells. Soon thereafter, Temin presented similar evidence for the incorporation of the RSV genome into infected cells, although others questioned his results. Temin's proposal that RSV becomes integrated into the DNA of an infected chicken cell genome as a provirus was met with intense skepticism for another reason.

The genome of RSV was known to be composed of RNA, not DNA. Studies of other viruses like polio and influenza had provided examples of RNA serving as a template for the production of more RNA. However, it was generally believed that the flow of information from DNA to RNA to protein was unidirectional. Temin's provirus hypothesis required the heretical conversion of viral RNA into DNA prior to integration and stable inheritance as part of host cell genomic DNA. Temin used inhibitors of DNA synthesis, RNA transcription from DNA, and protein synthesis to obtain evidence consistent with his hypothesis. Viral infection required DNA synthesis, but not protein synthesis. By contrast, viral production by infected cells required RNA synthesis but not DNA synthesis ( Fig. 7 ). Further evidence for a DNA intermediate in viral replication was provided in 1970 by the experiments of David Boettiger in the Temin laboratory. He showed that incorporation of 5-bromodeoxyuridine, a thymidine analog, into the virus caused it to become sensitive to inactivation by ultraviolet light. Similar experiments were also reported by Piero Balduzzi, John Bader, and Herbert Morgan.

Experimental evidence for Temin's provirus hypothesis. Viral infection was prevented by inhibitors of DNA synthesis, but not inhibitors of protein synthesis. By contrast, virus production was prevented by an inhibitor of RNA transcription (actinomycin D), but not by inhibitors of DNA synthesis. (Reprinted from Temin H. 1972. Proc Natl Acad Sci 69: 1016–1020.)

Meanwhile, the criticism had been fierce and unrelenting. Michael Bishop, who would eventually propose his own controversial hypothesis about RSV, described his first encounter with Howard Temin at a scientific meeting in 1968 as follows:

The hypothesis had earned him little but ridicule and grief. So that summer evening, I watched with interest (and from a respectful distance) as Howard argued long into the night with skeptics and detractors. It was my first experience with a scientist who was essentially alone in his beliefs. What I witnessed was a lesson for a lifetime. The opposition to the provirus hypothesis that evening was strong, even vitriolic. In response, Howard was unfailingly patient and reasoned. He had no doubt that his hypothesis was correct, but he was open to constructive criticism, and he painstakingly tried to refute each opposing argument, even those that had no force other than their animus.

Eventually Temin proved to be right. In 1970 he and Satoshi Mizutani reported the existence of an enzyme within detergent-disrupted RSV virions that could indeed convert RNA into DNA. An RNA-dependent DNA polymerase was independently discovered in a murine leukemia virus by David Baltimore, a virologist who had also trained with Renato Dulbecco and was studying the mechanisms of replication of different types of animal viruses. The result was a scientific earthquake, similar in magnitude to that of New Madrid in 1812, which was said to have caused the Mississippi River to run backward. Because of the unprecedented reversal of flow of genetic information from RNA to DNA, this new viral enzyme became known as “reverse transcriptase.” The RNA tumor viruses that encode this enzyme became known as “retroviruses.”

Physical proof of the existence of a DNA provirus came shortly thereafter. Jan Svoboda, a talented virologist, had persisted in studying the biology of RSV behind the Iron Curtain in what was then Czechoslovakia. In the early 1960s he and his colleagues had been able to transform rat fibroblasts by coculture with RSV-infected chicken cells. However, the rat cells themselves were unable to produce infectious RSV unless fused to normal chicken cells. Although these findings supported the provirus theory, Temin himself remained skeptical of this evidence. In 1972, using the same methods and logic by which Oswald Avery and colleagues had first shown that DNA was the genetic material of bacteria, Miroslav Hill and Jana Hillova sealed the deal. They showed that purified genomic DNA from rat cells transformed by RSV could be introduced into uninfected chicken cells, resulting in the production of infectious RSV.

In 1975, Temin and Baltimore received a Nobel Prize in Physiology or Medicine for the discovery of reverse transcriptase, a prize they shared with their mentor Renato Dulbecco for his (and Marguerite Vogt's) work on polyomavirus. Along with the awarding of a Nobel Prize to Peyton Rous in 1966 for the discovery of RSV, this event prompted Peter Duesburg (a fellow retrovirologist) to quip, “One sick chicken, two Nobel prizes.” But that was hardly the end of the story.

From the forthcoming volume Stalking the Enemy Within: A History of Cancer Research , by Joseph Lipsick

Additional Perspectives on A History of Cancer Research available at www.cshperspectives.org

SUGGESTED READING

The phage school, cell culture, and the birth of quantitative animal virology.

• Dulbecco R, Vogt M. 1954. Plaque formation and isolation of pure lines with poliomyelitis viruses . J Exp Med 99 : 167–182. 10.1084/jem.99.2.167 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Eagle H. 1955. Nutrition needs of mammalian cells in tissue culture . Science 122 : 501–514. 10.1126/science.122.3168.501 [ PubMed ] [ CrossRef ] [ Google Scholar ]
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• Skloot R. 2010. The immortal life of Henrietta Lacks . Crown/ Random House, New York. [ Google Scholar ]
• Watson JD, Stent GS, Cairns J. 2000. Phage and the origins of molecular biology . Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. [ Google Scholar ]

The Discovery and Assay of RNA Tumor Viruses

• Coffin JM, Hughes SH, Varmus HE editors. 1997. Retroviruses . Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. [ PubMed ] [ Google Scholar ]
• Ellermann V, Bang O. 1909. Experimental leukemia in chickens II . Z Hygiene Infektionskrakheiten 63 : 231–272. [English translation available in Some classics in experimental oncology (ed. Shimkin M), NIH Publication No 80-2120 (1980)]. 10.1007/BF02227892 [ CrossRef ] [ Google Scholar ]
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The Discovery of Reverse Transcriptase

• Baltimore D. 1970. RNA-dependent DNA polymerase in virions of RNA tumour viruses . Nature 226 : 1209–1211. 10.1038/2261209a0 [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Temin HM, Mizutani S. 1970. RNA-dependent DNA polymerase in virions of Rous sarcoma virus . Nature 226 : 1211–1213. 10.1038/2261211a0 [ PubMed ] [ CrossRef ] [ Google Scholar ]

The Provirus Hypothesis

• Baltimore D. 1995. Thinking about Howard Temin . Genes Dev 9 : 1303–1307. 10.1101/gad.9.11.1303 [ PubMed ] [ CrossRef ] [ Google Scholar ]
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The Search for Human Tumor Viruses

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• Wade N. 1971. Special virus cancer program: travails of a biological moonshot . Science 174 : 1306–1311. 10.1126/science.174.4016.1306 [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Zur Hausen H. 2009. The search for infectious causes of human cancer: where and why? Virology 392 : 1–10. 10.1016/j.virol.2009.06.001 [ PubMed ] [ CrossRef ] [ Google Scholar ]

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Carolina Strong: Woman makes strides in breast cancer community in honor of late mother

CHARLOTTE — Laura Renegar’s mother was just 61 when she lost her third battle with breast cancer.

More than a decade later, Renegar found herself on a life-changing path by walking in the American Cancer Society’s Making Strides Against Breast Cancer event .

She said it was something she always wanted to do in honor of her mother.

“She was amazing. She was the best grandma in the entire world,” Renegar said. “And we did the walk in 2008, 2009, and 2010. And then I was diagnosed.”

By the time of her diagnosis, Renegar said she had become a leader on her team.

“People looked at me and thought, ‘That team leader, she could be diagnosed; I could be diagnosed.’ And when I started hearing that, I decided to take that and push forward,” Renegar said.

As a survivor, she said she has become a force in the breast cancer community.

“We started off our first year; I think we raised $10,000. And we had 50 walkers, and our highest team membership has been 375 walkers. And we’ve raised a million and a half dollars so far,” she explained.

>> Renegar explains the various ways she has helped hundreds of newly diagnosed women, in the video at the top of the page.

Every day, there are people across the Carolinas doing extraordinary things. They’re giving back, they’re helping each other, and they’re making a real difference. We’re highlighting the best in our community in our series, Carolina Strong.

Know somebody who’s making a positive impact? Let us know here .

Carolina Strong: Student raises money for cancer research in honor of mother’s leukemia diagnosis

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Everything you need to know about Glyphosate and RoundUp safety

• EPA's Review of Glyphosate Safety

There is much discussion about glyphosate, the active ingredient in most Roundup® brand herbicides and other weed-control products. Is it safe to use? What impact does it have on the environment? And more.

By sharing fact-based information and scientific findings from numerous independent sources, we want to show you that glyphosate is safe to use as directed and does not cause cancer in humans. 

Glyphosate-based herbicides are among the most widely-used crop protection products. For 50 years, it has been approved and used safely in modern agriculture and food production, vegetation management, lawn care, gardening and more.  

Due to its extensive history, rigorous testing and oversight, it’s one of the most studied herbicides in the world.  

All crop protection products, including glyphosate, are subject to rigorous testing and oversight by regulatory agencies worldwide. Regarding safety assessments, glyphosate-based herbicides are among the most extensively tested products, with more than 1,500 studies and 50 years of research. After reviewing the volume of scientific research and evaluations by regulatory agencies over the years, experts and regulators worldwide have concluded that glyphosate-based products can be used safely as directed.

As the population grows, the agricultural industry is continuously working to grow healthy crops with less impact on the environment. That means using less land and natural resources, preserving biodiversity, reducing greenhouse gas emissions and helping to ensure that soil stays rich with nutrients.

Providing farmers with tailored solutions designed to address these challenges is crucial. Glyphosate-based products provide efficient and safe crop protection. 

Bayer stands fully behind our glyphosate-based Roundup® products, which have been used safely and successfully around the world for 50 years.

Glyphosate-based herbicides are the most widely used and extensively tested herbicides on the market, which is a major reason why so many farmers and others around the world continue to rely on these products not only for effective weed control, but also to minimize tillage farming practices, reduce greenhouse gas emissions, preserve more land for native habitats, and provide enough food to meet the needs of a growing population worldwide.

Like all herbicides, glyphosate has been subject to rigorous testing and oversight by regulatory authorities. The leading health regulators around the world have repeatedly concluded that glyphosate-based products can be used safely as directed. Most recently, in November 2023, the EU Commission re-approved glyphosate for 10 years, following the favorable scientific assessments by its health and safety agencies, including the European Chemicals Agency (ECHA) and European Food Safety Authority (EFSA) , which “did not identify any critical areas of concern.” The U.S. Environmental Protection Agency (EPA) and the regulatory authorities in Japan , Australia , Korea , Canada , New Zealand , and elsewhere have also recently reaffirmed that glyphosate-based products can be used safely as directed.

For details about the U.S. litigation: www.Bayer.com/5pointplan .