Study identifies novel genomic changes in the most common type of lung cancer
TCGA finds mutations in a key cancer-causing pathway, expanding targets for existing drugs
Researchers from the Broad Institute and elsewhere have identified novel mutations in a well-known cancer-causing pathway in lung adenocarcinoma, the most common subtype of lung cancer. Knowledge of these mutations could potentially identify a greater number of patients with treatable mutations because many potent cancer drugs that target these mutations already exist. In addition, these findings may expand the number of possible new therapeutic targets for this disease.
In this new study, published online July 9, 2014, in the journal Nature, researchers from the Cancer Genome Atlas (TCGA) Research Network, under the direction of Broad senior associate member Matthew Meyerson, examined the genomes, RNA, and some protein from 230 lung adenocarcinoma samples. In three-quarters of the samples, the scientists ultimately identified mutations that put a cell-signaling pathway known as the RTK/RAS/RAF pathway into overdrive.
“Lung adenocarcinoma is the leading cause of human cancer death. This is because there are so many ways to develop the disease, and many different pathways are altered in this cancer,” said Meyerson, who is also a professor of pathology at Harvard Medical School and the Dana-Farber Cancer Institute. “In recent years, we have made enormous progress in lung adenocarcinoma treatment by targeting EGFR, ALK, and other mutated proteins. Through this study, we are able to add to the range of such alterations and therefore gain potential new therapeutic targets.”
Mutations affecting the RTK/RAS/RAF pathway can cause it to become stuck in the “on” state. As a result, signals that promote cancer cell proliferation and survival are produced continuously. However, drugs are currently available that curb aberrant activity of this pathway and prompt therapeutic responses in patients.
“About 10% of patients have tumors with EGFR mutations, and these patients uniquely benefit from anti-EGFR therapy,” said Alice Berger, a post-doctoral fellow in the Meyerson lab and co-author of the study. “We were motivated to find genetic aberrations in patients that lack EGFR mutations and that might be similarly suitable for therapeutic targeting. Ultimately, we want to be able to provide every patient with an effective drug for their specific cancer.”
In the group’s initial scan of the tumor samples, researchers identified gene mutations that would increase RTK/RAS/RAF pathway activity in 62 percent of the samples. The affected genes are oncogenes, or genes that have the potential to cause cancer when mutated or expressed at high levels. Consequently, these tumor samples were classified as oncogene-positive. To identify additional alterations, the investigators looked at DNA copy number changes, or changes in gene number resulting from the deletion or amplification (multiplication) of sections of DNA in the genome. In doing so, they detected amplification of two oncogenes, ERBB2 and MET, which are part of the RTK/RAS/RAF pathway in the “oncogene negative” cancers. Gene amplification usually leads to increased expression of the encoded protein in cells. Now that these amplifications have been identified in cancers without other activity of the RTK/RAS/RAF pathway, clinicians may be able to treat patients whose tumors have specific gene changes with drugs that are either currently available or under development.
“It is quite striking that we have now identified an actionable mutation in over 75 percent of patients with lung adenocarcinoma, a significant improvement from a decade ago,” said Meyerson.
Additional analysis identified other genes that may play important roles in lung cancer development. Mutations in one of these genes, NF1 — a known tumor suppressor gene that regulates the RTK/RAS/RAF pathway — had previously been reported in lung cancer. Mutations of NF1 also put that pathway into overdrive. Another mutated gene, RIT1, is also part of the RTK/RAS/RAF pathway, and this is the first study to associate mutation of this gene with lung cancer.
“This is one of the most comprehensive studies of lung adenocarcinoma to date,” said co-author Joshua Campbell, a post-doctoral fellow in the Meyerson lab. “The TCGA data enabled us to profile and analyze DNA, RNA, and methylation from over 200 tumors, and it made the discovery of these rare alterations possible.”
In the aggregate, the several forms of lung cancer comprise the most common cause of cancer-related deaths worldwide, with more than 1 million deaths annually. NCI estimates that only 17.5 percent of people diagnosed with lung cancer are still alive five years later. Lung adenocarcinoma, the most common form in the United States, develops in tissues near the outer parts of the lungs and can spread widely. Although smoking is the main risk factor, adenocarcinoma is also the most common type of lung cancer among lifelong non-smokers, and the risk of lung cancer is increased by 20 to 30 percent by exposure to secondhand smoke.
Other Broad researchers who contributed to this work include Joshua D. Campbell, Mara Rosenberg, Angela N. Brooks, Alice H. Berger, Carrie Sougnez, Andrew D. Cherniack, Juliann Chmielecki, Peter S. Hammerman, Kristian Cibulskis, Eran Hodis, Andrey Sivachenko, Mike S. Lawrence, Gordon Saksena, Robert C. Onofrio, Chandra Sekhar Pedamallu, Scott L. Carter, Bryan Hernandez, Rameen Beroukhim, Lynda Chin, Juok Cho, Daniel DiCara, Travis Zack, Marcin Imielinski, Nils Gehlenborg, David Heiman, Lee Lichtenstein, Petar Stojanov, Pei Lin, Will Mallard, Jaegil Kim, Helga Thorvaldsdottir, Chip Stewart, Doug Voet, Elena Helman, Marc-Danie Nazaire, Hailei Zhang, Jim Robinson, Lihua Zou, Jill Mesirov, Levi Garraway, Michael Noble, Stacey B. Gabriel, Gad Getz, and Eric S. Lander.
This work was supported by the following NIH grants: U24 CA126561, U24 CA126551, U24 CA126554, U24 CA126543, U24 CA126546, U24 CA137153, U24 CA126563, U24 CA126544, U24 CA143845, U24 CA143858, U24 CA144025, U24 CA143882, U24 CA143866, U24 CA143867, U24 CA143848, U24 CA143840, U24 CA143835, U24 CA143799, U24 CA143883, U24 CA143843, U54 HG003067, U54 HG003079 and U54 HG003273.
Paper cited: The Cancer Genome Atlas Network authors. Comprehensive Molecular Profiling of Lung Adenocarcinoma. Online July 9, 2014. DOI: 10.1038/nature13385.
About the TCGA
TCGA is jointly funded and managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both part of the National Institutes of Health. A TCGA analysis of another, less common form of lung cancer, squamous cell carcinoma, was reported in 2012. In addition to the two lung cancer studies, the TCGA Research Network has generated data and published analyses on a number of cancers, all of which can be found on the TCGA website, www.cancergenome.nih.gov. TCGA-generated data are freely available at the TCGA Data Portal and CGHub.
The TCGA Research Network consists of more than 150 researchers at dozens of institutions across the nation. A list of participants is available at http://cancergenome.nih.gov/abouttcga/overview. More details about The Cancer Genome Atlas, including Quick Facts, Q&A, graphics, glossary, a brief guide to genomics, and a media library of available images, can be found at http://cancergenome.nih.gov.
About the Broad Institute of MIT and Harvard
The Eli and Edythe L. Broad Institute of MIT and Harvard was launched in 2004 to empower this generation of creative scientists to transform medicine with new genome-based knowledge. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods, and data openly to the entire scientific community.
Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff, and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to www.broadinstitute.org.
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