Large-Scale Genetic Study Sheds New Light on Lung Cancer, Opens Door to Individualized Treatment Strategies
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A multi-institution team, funded by the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH), has reported results of the largest effort to date to chart the genetic changes involved in the most common form of lung cancer, lung adenocarcinoma.
The findings should help pave the way for more individualized approaches for detecting and treating the nation's leading cause of cancer deaths.
In a paper published in the Oct. 23 issue of the journal "Nature", the Tumor Sequencing Project (TSP) consortium identified 26 genes that are frequently mutated in lung adenocarcinoma - an achievement that more than doubles the number of genes known to be associated with the deadly disease. But the pioneering effort involved far more than just tallying up genes.
Using a systematic, multi-disciplinary approach, the TSP team also detailed key pathways involved in the disease, and described patterns of genetic mutations among different subgroups of lung cancer patients, including smokers and never-smokers.
"By harnessing the power of genomic research, this pioneering work has painted the clearest and most complete portrait yet of lung cancer's molecular complexities. This big picture perspective will help to focus our research vision and speed our efforts to develop new strategies for disarming this common and devastating disease," said NHGRI Acting Director Alan E. Guttmacher, M.D.
Like most cancers, lung adenocarcinoma arises from changes that accumulate in people's DNA over the course of their lives. However, little is known about the precise nature of these DNA changes, how they occur and how they disrupt biological pathways to cause cancer's uncontrolled cell growth.
To gain a more complete picture, researchers have joined together to form TSP and other large, collaborative projects that are using new tools and technologies to examine the complete set of DNA, or genome, found in various types of cancer.
"We found lung adenocarcinoma to be very diverse from a genetic standpoint. Our work uncovered many new targets for therapy of this deadly disease - oncogenes that drive particular forms of lung adenocarcinoma and tumor suppressor genes that would ordinarily prevent cancer cell growth," said Matthew Meyerson, M.D., Ph.D., a senior author of the paper. Dr. Meyerson is a senior associate member of the Broad Institute of MIT and Harvard and an associate professor at the Dana-Farber Cancer Institute and Harvard Medical School.
In the new study, the TSP team purified DNA from tumor samples and matching non-cancerous tissue donated by 188 patients with lung adenocarcinoma. Next, they sequenced the DNA to look for mutations in 623 genes with known or potential relationships to cancer. Prior to the study, fewer than a dozen genes had been implicated in lung adenocarcinoma. The latest research identified 26 new genes that are mutated in a significant number of samples. Most of these genes had not previously been associated with lung adenocarcinoma.
Among the genes newly implicated in lung adenocarcinoma are:
• Neurofibromatosis 1 (NF1). Mutations in this gene have previously been shown to cause neurofibromatosis 1, a rare inherited disorder characterized by unchecked growth of tissue of the nervous system.
• Ataxia Telengiectasia Mutated (ATM). ATM mutations have previously been shown to play a role in ataxia telangiectasia, which is a rare inherited neurological disorder of childhood, and in various types of leukemia and lymphoma.
• Retinoblastoma 1 (RB1). Past research has tied RB1 mutations to retinoblastoma, a relatively uncommon type of childhood cancer that originates in the eye's retina.
• Adenomatosis polyposis coli (APC). Mutations of this gene are common in colon cancer.
• Ephrin receptors A3 and A5 (EPHA3 and EPHA5), neurotrophin receptors (NTRK1 and NTRK3) and other receptor-coupled tyrosine kinases (ERBB4, KDR and FGFR4). These genes code for cell receptors coupled to members of the tyrosine kinase family of enzymes, which are considered prime targets for new cancer therapies.
After identifying the genetic mutations, the team went on to examine their impacts on biological pathways and determine which of those pathways were most crucial in lung adenocarcinoma. Such research is essential to efforts to develop new and better treatments for cancer.
