BETHESDA, Md.—Researchers from The Cancer Genome Atlas (TCGA) Research Network have discovered—and published their findings about—a novel mutation that could lead to significant gains in the treatment of lung adenocarcinoma, the most common subtype of lung cancer. The identification of genomic changes in a well-known cancer-causing pathway has the potential to expand therapeutic targets for the disease and enable a greater number of patients with treatable mutations to be given effective therapies.
“This paper is the latest in a series of reports from this program that have given us a much better understanding of the genetic pathways involved in lung cancer,” Dr. Adam Felsenfeld, program director of the Genome Sequencing Program at the National Human Genome Research Institute (NHGRI), tells DDNews.
TCGA’s research is jointly funded and managed by the National Cancer Institute (NCI) and the Genome Sequencing Program at the NHGRI. TCGA issued an analysis of another less common form of lung cancer, squamous cell carcinoma, in 2012.
NCI estimates that only 17.5 percent of people diagnosed with lung cancer survive beyond five years. Lung adenocarcinoma, the most common form of the disease in the United States, develops in tissues near the outer parts of the lungs and can spread widely. Smoking is the main risk factor of the disease, but it is also the most common type of lung cancer among lifelong non-smokers.
TCGA’s genomic sequencing of lung cancer is one component of its broader mission to reveal the molecular basis of cancer through the application of genome analysis technologies. “Tumors used to be classified mainly based on how they look under microscope, and we weren’t able to accurately understand why one patient survived longer than another with a similar-looking tumor,” Felsenfeld says. “Genomic sequencing is allowing us to catalogue and classify tumors more accurately and choose therapies in more logical ways.”
The latest study from TCGA, published online in Nature on July 9, examined the genomes, RNA and some protein from 230 lung adenocarcinoma samples. Scientists identified mutations in three-quarters of the samples that put a specific cell-signaling pathway, known as the RTK/RAS/RAF pathway, into overdrive. 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.
“Based on this knowledge, we can now seek better pathway inhibitors to improve patient outcomes,” NCI Director Harold Varmus has noted. “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.”
The researchers’ initial scan of tumor samples identified gene mutations that would increase RTK/RAS/RAF pathway activity in 62 percent of their samples. The affected genes were identified as having the potential to cause cancer when mutated or expressed at high levels.
The researchers identified additional alterations by looking at changes in gene number resulting from the deletion or amplification of sections of DNA in the genome. In doing so, they detected amplification of two cancer-causing genes, ERBB2 and MET, which are part of the RTK/RAS/RAF pathway. Gene amplification usually leads to increased expression of the encoded protein in cells. Now that these amplifications have been identified, clinicians may be able to treat patients whose tumors have specific gene changes with drugs 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 Harvard Medical School’s Matthew Meyerson, one of the lead investigators on the project.
Additional analysis by the researchers identified other genes that may play important roles in lung cancer development. Mutations in one of these genes, NF1, had previously been reported in lung cancer. NF1 is a known tumor suppressor gene that regulates the RTK/RAS/RAF pathway. Mutations in NF1 also put the 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.