Genotype-environment interactions in microsatellite stable/microsatellite instability-low colorectal cancer: results from a genome-wide association study

Figueiredo JC, Lewinger JP, Song C, Campbell PT, Conti DV, Edlund CK, Duggan DJ, Rangrej J, Lemire M, Hudson T, Zanke B, Cotterchio M, Gallinger S, Jenkins M, Hopper J, Haile R, Newcomb P, Potter J, Baron JA, Le Marchand L, Casey G (2011) Genotype-environment interactions in microsatellite stable/microsatellite instability-low colorectal cancer: results from a genome-wide association study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20:758-766

BACKGROUND: Genome-wide association studies (GWAS) have led to the identification of a number of common susceptibility loci for colorectal cancer (CRC); however, none of these GWAS have considered gene-environment (G x E) interactions. Therefore, it is unclear whether current hits are modified by environmental exposures or whether there are additional hits whose effects are dependent on environmental exposures. METHODS: We conducted a systematic search for G x E interactions using genome wide data from the Colon Cancer Family Registry that included 1,191 cases of microsatellite stable (MSS) or microsatellite instability-low (MSI-L) CRC and 999 controls genotyped using either the Illumina Human1M or Human1M-Duo BeadChip. We tested for interactions between genotypes and 14 environmental factors using 3 methods: a traditional case-control test, a case-only test, and the recently proposed 2-step method by Murcray and colleagues. All potentially significant findings were replicated in the ARCTIC Study. RESULTS: No G x E interactions were identified that reached genome-wide significance by any of the 3 methods. When analyzing previously reported susceptibility loci, 7 significant G x E interactions were found at a 5% significance level. We investigated these 7 interactions in an independent sample and none of the interactions were replicated. CONCLUSIONS: Identifying G x E interactions will present challenges in a GWAS setting. Our power calculations illustrate the need for larger sample sizes; however, as CRC is a heterogeneous disease, a tradeoff between increasing sample size and heterogeneity needs to be considered. IMPACT: The results from this first genome-wide analysis of G x E in CRC identify several challenges, which may be addressed by large consortium efforts.