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Comprehensive map of altered gene pathways in dozens of cancer types will guide research in precision cancer medicine

  • Analysis of The Cancer Genome Atlas data reveals distribution of commonly altered pathways in dozens of cancer types
  • Findings to play key role in developing clinical trials of targeted therapies and advancing personalized cancer therapy for patients

In the broadest-scale survey yet undertaken of abnormal genetic pathways in cancer, investigators at Dana-Farber Cancer Institute and other members of The Cancer Genome Atlas (TCGA) network have produced a guide to the genetic terrain of cancer that provides scientists with countless leads for the development and testing of new, personalized therapies.

The manuscript is part of the TCGA Program, a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI). The analysis, posted online today by the journal Cell, is one of 27 papers based on the TCGA project that are being published simultaneously in Cell Press journals. It is one of three TCGA "marker" papers that summarize key findings of more than five years of effort in the cancer research community.

Collectively, these publications, which draw on massive TCGA cancer genomics databases to probe the basic biology of cancer, represent the latest scientific progeny of TCGA, a seven-year project that genomically profiled more than 11,000 samples of tumor tissue and matched samples of normal tissue, to gain an understanding of cancer in unprecedented molecular detail. Completed in 2017, TCGA – a collaboration of hundreds of researchers at more than 20 institutions coordinated by the National Cancer Institute and the National Human Genome Research Institute and funded by the National Institutes of Health – generated data that has been used in more than a thousand cancer studies to date.

In their study, Dana-Farber investigators and their colleagues used TCGA data to trace patterns of abnormalities in molecular signaling pathways across a wide range of cancers. (Pathways are made up of molecules that signal one another to become more or less active. Like a missed connection in a string of Christmas lights, a mutation or defect in a single gene can disrupt the function of an entire pathway or group of interwoven pathways.) They then coupled that data with information from scientific databases about drug agents that target specific abnormal genes and proteins. The result is not only a map of abnormal pathways in multiple types of cancer, but also a directory of drugs – both approved and in the testing stages – that might be effective for those cancers.

"Alterations in signaling pathways that control how a cell behaves, such as division, growth, and death, are a common feature of cancer, but there is a great deal of variation in which of these alterations arise in specific types of cancer," says Dana-Farber's Chris Sander, PhD, a co-senior author of the study with Nikolaus Schulz, PhD, of Memorial Sloan Kettering Cancer Center (MSKCC); Eliezer Van Allen, MD, of Dana-Farber; Andrew D. Cherniak, PhD, of the Broad Institute of MIT and Harvard; and Giovanni Ciriello, PhD, of the Swiss Cancer Center Lausanne and University of Lausanne. "In our study, we used TCGA data to map some of the most commonly altered pathways in a range of cancer types, and to integrate our findings with information on drug therapies targeting specific abnormal genes and proteins."

Sander and his colleagues analyzed seven different types of genomic and molecular data generated by TCGA for abnormalities in any of 10 major pathways linked to cancer. The abnormalities included mutations in cancer-related genes; over- or underexpression of such genes; extra or missing copies of such genes; and fusions of genes that lead to cancer-promoting proteins. The investigators charted these altered pathways across 33 types of cancer, divided into 64 subtypes, and looked for alterations that were common in many cancer types, as well as those that arose in only a few types.

"We found that 89 percent of tumors had an alteration in at least one of these pathways known to contribute to cancer growth," Sander relates. "Fifty-seven percent had at least one alteration that can potentially be targeted by currently available drugs, and 30 percent had more than one targetable alteration, indicating opportunities for therapy combining multiple drugs."

Sander explains that linking these findings to information on drugs targeting specific genetic aberrations promises to help researchers in a number of ways. It can help physicians assign patients to precision medicine clinical trials and make better-informed decisions about the optimal choice of therapy, as well as aid in the design of future trials.

It may also help predict which patients are at risk of developing resistance to particular therapies and identify combinations of therapies capable of overcoming that resistance.

In addition to offering a compendium of knowledge about the distribution of pathway alterations across dozens of cancer types, the study also underscores where more research is needed, Sander remarks. Genomic analysis of more tumor samples is necessary to track rare alterations.

"Our findings will help set the agenda for future research in the molecular biology of cancer, as well as guide investigators in identifying the most promising targets and their combinations for new drug therapies and in testing those therapies in clinical trials," Sander states.

The lead authors of the study are Francisco Sanchez-Vega, PhD, of MSKCC, Marco Mina, PhD, of the Swiss Cancer Center Lausanne and University of Lausanne, and Joshua Armenia, PhD, of MSKCC. 

 

Posted on April 05, 2018

  • Research

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