Abstract 2194: Genome-wide gene-environment interactions study on colorectal cancer
Authors: Victor Moreno, Ulrike Peters, Li Hsu, Jian Gong, Yi Lin, Bhramar Mukherjee, Graham Casey, Duncan Thomas, Stephen B. Gruber, Jim Gauderman
Journal: Cancer Research (2014)

Abstract Susceptibility loci identified so far for colorectal cancer (CRC) only account for a small fraction of the estimated inheritance. Since most GWAS performed only have focused on associations between genetic variants and cancer risk, it is possible that the penetrance of a relevant fraction of inherited risk is conditional on certain environmental exposures. Here we have undertaken an exhaustive analysis of gene-environment (GxE) interactions aiming to identify novel susceptibility loci for CRC. More than 10,000 cases and 10,000 controls from 11 GWAS studies have been analyzed within the ColoRectal Transdisciplinary Study (CORECT) and Colon Cancer Family Registries (CCFR) Consortia. These subjects have been genotyped with diverse dense SNP arrays that have been imputed to the 1000 Genomes Project panel. After a QC and filtering protocol (MAF&amp;gt;0.01, LD&amp;lt;0.99), more than 4.5 million SNPs have been analyzed for GxE interactions in relation to known and potential environmental factors for CRC: smoking, height, BMI, aspirin/NSAIDs, hormones, alcohol, calcium, folate, vegetables, fruits, red meat, and processed meat. All environmental risk factors have been centrally harmonized through a standardized process and individual level data are available for all analysis. Diverse statistical models have been used to scan for GxE interaction, including logistic regression for case-control (CC), case-only (CO) analysis, empirical Bayes (EB), as well as more powerful 2-step procedures, such as the cocktail (Hsu et al., 2012) and EDGxE (Gauderman et al., 2013) methods. All of these procedures were implemented in the GxEScan software program (http://biostats.usc.edu/software). A weighted testing approach has been used for two-step methods to improve the likelihood of capturing significant interactions while multiple testing is controlled. Significant SNPs identified by each method are ranked and a weighted procedure is used to capture interactions more likely to be real. Each study is analyzed in parallel and results are combined using meta-analysis techniques. Initial analysis of a subset of the studies suggests genome-wide significant interaction for multiple environmental risk factors, which we are currently following up across all studies. Conclusions: This large, well-powered analysis will provide detailed results on gene-environment interactions across all the genome for multiple environmental risk factors and shed light on the contribution of GxE interactions to colorectal cancer risk and our understanding of the underlying biologic processed leading to the development of this diseases. Citation Format: Victor Moreno, Ulrike Peters, Li Hsu, Jian Gong, Yi Lin, Bhramar Mukherjee, Graham Casey, Duncan Thomas, Stephen B. Gruber, Jim Gauderman, on behalf of CORECT and CCFR. Genome-wide gene-environment interactions study on colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2194. doi:10.1158/1538-7445.AM2014-2194