Identifying a Reversible Genetic Factor that Drives Lung Cancer in Veteran African Americans to Foster the Early Detection and Prevention of Lung Cancer
Abstract
The genetics of cancer development has been linked to a diverse set of gene polymorphisms. By statistical analysis, a number of these different polymorphisms have been associated with cancer risk. Many of these potential markers of cancer risk, however, either have a low cancer association or it is not understood how they functionally impart changes in gene expression that result in increased cancer risk. We have identified two polymorphisms that underlie the epigenetic regulation of the BRM gene, the loss of which is known to be involved in lung cancer. Epigenetic regulation of genes involves the turning off and on of genes and is the primary mechanism in differentiation and development. Epigenetic mechanisms are now thought to play a much larger role in many solid tumors than previously understood. Defining these epigenetic mechanisms and their role in cancer growth is essential effective implement tools to improve the detection of early lungs and for the development of accurate risk assessment as well as novel forms of therapy. A critical barrier in developing risk assessments and surveillance for lung cancer is our lack of understanding of the roles of these genetic factors. This is particularly true since CT (computed tomography) scan has been demonstrated to detect early lung cancers and thus improve survival. But to use CT scan on everyone thought to be at risk for lung cancer, for example, all smokers, would be cost-prohibitive and furthermore introduce additional risk from exposure to radiation. Thus, it is essential to discern those at greatest risk for lung cancer. While polymorphisms are known to underlie cancer risk, and hundreds have been identified via GWAS (Genome Wide Association Studies) studies, a majority of individual GWAS polymorphisms have little to no mechanistic connection and relatively low impact on cancer risk (low odds ratios <1.3); thus, they likely have a low impact on potentiating cancer. In contrast, we have identified a unique set of polymorphisms within the promoter region of the anticancer BRM gene. These polymorphisms recruit a cadre of proteins to silence the BRM gene. As BRM is an essential cofactor for DNA repair and growth inhibition, its silencing via the presence of these polymorphisms may explain why these polymorphisms repeatedly predict cancer risk in Caucasians. Specifically, the study of BRM polymorphism because of their high association with cancer risk will help us understand the molecular mechanisms of early progression to clinically significant lung cancer. Compared with Caucasians, African Americans have consistently higher lung cancer rates -- up to 34% -- despite similar smoking rates. They also have lower rates of EGFR mutations than Caucasians but higher rates of EGFR resistance mutations. Interestingly, however, recent comparisons of younger African Americans and Caucasians who did not smoke show that overall mortality rates from smoking have decreased more for African American males (by 41%) and females (by 35%). Hence, smoking appears to affect lung cancer rates in African Americans more than other groups. It is therefore important to evaluate the role of BRM polymorphisms in Veteran African American populations given their disproportional risk of lung cancer. The rationale for this research is based upon the observations that (1) these polymorphisms are more frequent in African Americans, and (2) they are more predictive of cancer risk in Caucasians than the majority of other known GWAS polymorphisms. We hypothesize that the higher inherited frequencies of these two BRM polymorphisms explains why African Americans and potential veterans have a much higher risk of lung cancer though they have lower smoking rates than non-Veteran Caucasians. To test this hypothesis, we will genotype Caucasians and African American non-Veteran and Veterans subjects and matched controls to determine the relative risk of developing lung cancer in those with t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610275
Entities
People
- David Reisman
Organizations
- United States Army
- University of Florida