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Abstract IA10: Deciphering the signals from the GWAS hits: From function to epidemiology and back again.

Abstract Genome wide association studies (GWAS) have identified hundreds of single nucleotide polymorphisms (SNPs) that confer susceptibility to a multitude of complex, multifactorial disease traits including cardiovascular disease, diabetes, and several cancers. For the vast majority of identified common genetic variants, the functional rationale underlying disease is largely unknown. The functional effects of common risk associated SNPs are likely to be subtle given that they confer smaller risks (ORs <1.2). More than 90% of confirmed common risk-SNPs lie in non-coding DNA, often several kilobases from the nearest gene suggesting a critical role for non-coding DNA in the functional influence of these SNPs. A significant focus of functional follow-up studies at common susceptibility loci has therefore been to understand the interplay between non-coding DNA elements such as regulators and enhancers, non-coding RNA species such as micro- and long non-coding RNAs, and risk associated germline variants. GWAS studies have also highlighted regions of the genome that contain plausible cancer susceptibility genes that may be specific to disease etiology (e.g. the FGFR gene in breast cancer), and other genes that may play more general role in cancer (e.g. the TERT gene, multi-cancer risk locus). The current presentation will focus on ovarian cancer. The Ovarian Cancer Association Consortium (OCAC) has identified 11 confirmed susceptibility loci, and suggest multiple candidate genes that have either previously been implicated in ovarian cancer development, or function in pathways such as double strand DNA break and nucleotide excision repair, which suggests they may play a significant role in ovarian cancer risk and/or clinical outcome. Data presented will describe approaches to understanding the functional role of both susceptibility SNPs and candidate genes in the underlying cellular etiology of different subtypes of ovarian cancer, and provide evidence suggesting a role of candidate genes in disease initiation and treatment response. Overall, these studies highlight the challenges we face in the developing field of functional-epidemiology, in particular in understanding common low-penetrance susceptibility loci. However, the emerging data also provide support for the role of GWAS in unearthing critical, previously unknown mechanisms that underlie cancer biology, suggesting these studies may have a substantial clinical impact in the future. Citation Format: Simon A. Gayther. Deciphering the signals from the GWAS hits: From function to epidemiology and back again. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA10.