Genome-wide association studies (GWAS) provide the initial evidence that a genetic region harbors a cancer susceptibility locus. However, further research is needed to identify the causal variant(s) and understand the biology of complex diseases. The National Cancer Institute GAME-ON Network consists of five collaborating groups that pursue promising scientific leads from previously generated cancer GWAS and coordinate and accelerate integrative post-GWAS discovery research. The five site-specific groups are ColoRectal Transdisciplinary Study (CORECT), Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE), Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE), Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI), and Transdisciplinary Research in Cancer of the Lung (TRICL).

Each GAME-ON group is structured into three components: 1) Discovery and replication, which works to find new associations through pooled analyses, conducting GWAS in minority populations, independent replication of associations, and fine mapping of association signals; 2) Biological studies, which focus on evaluating risk-modifying variants, determining the biological mechanisms of risk-enhancement, and understanding the functional consequences of variants; and 3) Epidemiology, to evaluate gene-gene and gene-environment interactions, assess penetrance and population attributable risk, and develop risk models and evaluate their clinical validity.

Six working groups were formed to facilitate collaborations and share methodological expertise across all groups: 1) Analytic and Risk Modeling, to develop analytic tools, share analytic approaches, develop and validate models to characterize risk factors for cancer, 2) Epidemiology and Clinical, to plan and assist collaborative epidemiologic analysis, such as analyzing pan-cancer genes or pathways common to many cancers and the use of standard control sets across consortia, 3) Functional Assays, to share approaches for the characterization of functional consequences of risk variants, including identification of specific gene targets and their interaction mechanisms, 4) Next-Generation Genomic Technologies, to evaluate current and emerging technologies and platforms for optimal genotyping and sequencing, and assist in the search for less common and rare variants, 5) Epigenetics, to explore modification of genetic expression from epidemiological factors, and 6) the hTERT working group, to evaluate the impact of hTERT variations on risk across multiple cancer sites. Descriptive data for the ongoing projects will be presented.

In the past two years, GAME-ON has developed a network infrastructure for post-GWAS research, which will provide an inventory of epidemiologic and clinical data as well as availability of blood and tissue samples. Each group has identified new GWAS variants, completed meta-analyses, and developed strategies for fine-mapping and functional characterization of novel loci. Utilizing the collaborative environment of the network, researchers are currently developing a GAME-ON Oncochip with SNP selection from breast, colon, prostate, ovarian, and lung cancer variants, which will be used to genotype a large and diverse group of cancer cases and controls. Members of GAME-ON have used data from The Cancer Genome Atlas (TCGA) to implement eQTL analyses, conducted methylation and copy number expression analyses, and developed and applied novel methods for gene-environment interaction and pathway analysis. Major achievements and challenges within the past two years will be discussed.

Citation Format: Brett M. Kaminski, Christopher I. Amos, Eric DeRycke, Elizabeth M. Gillanders, Stephen B. Gruber, Brian E. Henderson, David J. Hunter, Pascale K. Lepage, Thomas A. Sellers, Daniela Seminara. Genetic Associations and Mechanisms in Oncology (GAME-ON): A network approach to post-GWAS research. [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 78.