Abstract IA19: The GAME-ON (Genetic Associations and Mechanisms in Oncology) Consortium: Assessing the functional relevance of genetic variation.

Abstract

Abstract Recently, significant advances in genetics, in particular in genome-wide association studies (GWAS), have uncovered a large number of chromosomal loci associated with cancer risk. Despite these advances the determination of the molecular mechanism behind the detected associations has proven to be a significant challenge. The design of most GWAS genotyping chips take advantage of well characterized tagging single nucleotide polymorphisms (SNPs). These “tags” represent specific proxy markers for a series of other SNPs in high linkage disequilibrium with the tagging SNP in a defined chromosomal region. While the use of tagging SNPs result in reproducible and robust signals during genotyping and minimize the number of SNPs to be tested, the expectation is that they may not necessarily constitute the causal SNP, the nucleotide change that result in a relevant biological activity responsible for cancer predisposition. Identification of predisposition loci in prostate, ovary, and breast have been accelerated by the COGS (Collaborative Oncologic Gene-Environment Study) project which typed 200,000 SNPs and genotyped an unprecedented number of cancer cases and controls (˜200,000). The GAME-ON (Genetic Associations and Mechanisms in Oncology) consortium has poured over GWAS data for prostate, ovary, breast, lung, and colorectal cancers to develop systematic procedures to dissect functional contribution of SNPs and their target genes. Here I describe our experience in conducting functional analyses for these loci, focusing on ovarian cancer susceptibility loci. The overall approach can be loosely divided in three stages: in the first we use the most significant SNP found in GWAS analyses or meta-analyses as a starting point to interrogate other candidate functional SNPs in the region. The second stage explores potential target genes in the region. Finally, we focus on tying the candidate functional SNP to the candidate target gene. This final stage may also focus on, depending on the availability of in vivo models, attempts to uncover direct evidence for the participation of the SNP/target gene pairs in the mechanism of oncogenesis. Although in some cases the analytic approaches and tools might be specific to the cancer in question, we feel that the main framework can be utilized for different cancers. Most importantly, perhaps, are the lessons learned during this process as well as identifying the limitations and challenges that lay ahead. Citation Format: Alvaro N.A. Monteiro. The GAME-ON (Genetic Associations and Mechanisms in Oncology) Consortium: Assessing the functional relevance of genetic variation. [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 IA19.