Abstract 1117: Who's in the driver's seat? Identifying causative variants of colorectal cancer

Abstract

Abstract Colorectal Cancer (CRC) is one of the leading causes of mortality in the US, being the third most common cancer among both men and women. While an exact cause of CRC has not yet been elucidated, the existence of a clear heritable genetic component has been established. With the recent surge of data from Genome-Wide Association Studies, a handful of CRC-associated loci have been identified via tagSNPs. While the probability of the tagSNPs themselves being the causative variants is low, the key may lie among the number of single-base variants linked to each tagSNP. It is crucial, in order to enhance our understanding CRC tumorigenesis, to extract these functional variants from the pool of associated SNPs and validate their causative significance within the cell. This project combines bioinformatics and functional experiments to both identify and assess the role of functional variants in CRC pathogenesis. One of the major hurdles in understanding the role of CRC risk-associated SNPs is the fact that virtually all variants lie in Non-Protein Coding Region, often tens of thousands of bases away from flanking genes. By combining variant data from publically available databases, such as that of the ENCODE project, this research presents a method to prioritize all variants within a set of disease-associated loci based on potential regulatory functionality in silico. With this technique, we have identified a handful of SNPs with functional potential that may be functioning specifically in CRC initiation. In parallel, we are in the process of developing a method to effectively produce isogenic cell lines modeling the appropriate variant alleles, utilizing the CRISPR/Cas9 system to stimulate homologous recombination in the presence of a donor template. With this method, transcriptional and regulatory changes within the cell due to the single-base genomic edit can be measured in order to characterize these functional variants. Utilizing this technology, we have been able to create our first SNP model of SNP rs6983267, a known functional variant whose risk SNP promotes CRC development by means of increased binding and activation of WNT signaling pathway elements, c-Myc and β-Catenin. The ultimate goal of this project is to better understand the role of CRC risk-associated variants, the result of which could have substantial clinical relevance in the generation of new therapies and diagnostics for the treatment of CRC. Citation Format: Nicole Coggins, Luis Carvajal-Carmona, David Segal. Who's in the driver's seat? Identifying causative variants of colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1117. doi:10.1158/1538-7445.AM2015-1117