Scientists from The Cancer Genome Atlas (TCGA) research network say they have identified novel mutations in a well-known cancer-causing pathway in lung adenocarcinoma, the most common subtype of lung cancer. Knowledge of these genomic changes may expand the number of possible therapeutic targets for this disease and potentially identify a greater number of patients with treatable mutations because many potent cancer drugs that target these mutations already exist, according to the researchers.
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 this new study (“Comprehensive molecular profiling of lung adenocarcinoma”), published online in Nature, researchers 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.
“DNA and mRNA sequence from the same tumor highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases,” wrote the investigators. “MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.”
“The integrated nature of TCGA analysis made these findings and their potential therapeutic implications possible,” said NIH director Francis S. Collins, M.D., Ph.D. “We hope this lays the groundwork for future work in precision medicine.”
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, some drugs currently available curb aberrant activity of this pathway and prompt therapeutic responses in patients.
“Combined with the earlier TCGA analysis of squamous lung cancers, we now have a comprehensive understanding of many of the genetic pathways that lead to cancers of the lung,” said NCI director Harold Varmus, M.D. “Based on this knowledge, we can now seek better pathway inhibitors to improve patient outcomes. However, for the time being, stopping smoking or never starting remain the most reliable ways to reduce the number of deaths due to lung cancer.”