Establishing BRM Polymorphisms as Predictive Biomarkers for Lung Cancer Risk

DESCRIPTION (provided by applicant): While there is no doubt smoking is a direct causative factor underlying the development of lung cancer, not every smoker develops lung cancer. In fact, only 10-15% of smokers develop this disease, indicating that otherfactors make certain individuals more susceptible to cancer. A number of single nucleotide polymorphisms are known to correlate with the development of lung cancer, but the underlying genes responsible for this association are not always clear. Nor is theimpact of any one of these polymorphisms by themselves known to be highly significant. Indeed, as of yet there are no known genes that have been convincingly associated with lung cancer. Our research has focused on the SWI/SNF complex, which controls and regulates gene expression for a number of proteins and signaling pathways that have anticancer functions. We have found that the inactivation of this complex-particularly via loss of its key catalytic subunit, BRM-promotes cancer development. BRM epigeneticsilencing occurs in 15-20% of most solid tumors. Intriguingly, this gene is epigenetically silenced but never mutated in cell lines or primary tumors. Central to the silencing of BRM are two polymorphisms found in the promoter region. Because these polymorphisms appear to control the silencing of BRM, we surmise their presence is secondarily associated with cancer. This research will use three independent case-control studies (~500 test subjects each) using different geographic populations to directly test whether these polymorphisms are indeed associated with lung cancer. We will genotype lung cancer patients and compare these results with a matched set of subjects who do not have a history of any type of cancer. Samples will be analyzed using an established TaqMan assay to determine genotypes and the specific BRM polymorphisms associated with lung cancer. This research would be a major advance not only because it could identify one of the first genes specifically associated with lung cancer, but also because this gene is epigenetically silenced and not mutated. Thus, it may be possible to reactivate BRM and eliminate this risk factor. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Using no more than two or three sentences, describe the relevance of this research to public health. In this section, be succinct and use plain language that can be understood by a general, lay audience confirming that the newly discovered BRM polymorphism correlates with cancer risk would lead to substantial progress in our ability to fight lung cancer. This potential marker will allow us to determine who is at higher risk for developing cancer, as well as allow us in the short term to stratify patients for cancer screening and chemoprevention. In the longer term, this work may help us develop targeted therapies to treat lung cancer more effectively.