Abstract 2198: A literature-based sum score of genetic variants in IGF genes modifies associations between indicators of energy balance and colorectal cancer risk

Abstract

Abstract Background: Gene-environment interactions between variants in growth-regulating IGF genes and energy balance in colorectal cancer (CRC) were studied in the Netherlands Cohort Study (NLCS) after 16.3 years follow-up. Methods: Using a systematic strategy, we selected 25 SNPs and a CA repeat in IGF genes that had repeatedly demonstrated significant associations with CRC risk, energy balance-related exposures or related endpoints in literature, and thus likely modify effects of energy balance on CRC development. Twenty-four SNPs were successfully genotyped in toenail DNA of NLCS subcohort members (n=3,203) and CRC cases (n=2,274) with adequate exposure data. Unfavorable alleles were aggregated into a sum score. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated in case-cohort analyses for linear combinations between tertiles of the genetic sum score and 8 energy balance-related exposures. Results: Significant and increasingly higher risks were observed for men with more adverse profiles compared to men with the most optimal profile. In particular carrying more unfavorable alleles in combination with a larger adult trouser/skirt size, an increased height or the absence of early life energy restriction during the Dutch Hunger Winter (1944-45) was associated with distal colon cancer [highest vs. lowest linear combinations: HR (95% CI) = 2.03 (1.27-3.24), 2.05 (1.16-3.63) and 1.87 (1.11-3.16), respectively]. A combined effect of IGF polymorphisms and energy balance-related exposures on subsite-specific CRC risk was less convincing in women. Conclusion: Combined effects of IGF polymorphisms and specific energy balance-related exposures are important in CRC development in men, and less convincingly in women. The availability of extensive environmental data and the aggregation of genetic variants were invaluable for interpreting the joint associations. Note: This abstract was not presented at the meeting. Citation Format: Colinda CJM Simons, Leo J. Schouten, Roger Godschalk, Frederik-Jan van Schooten, Piet A. van den Brandt, Matty P. Weijenberg. A literature-based sum score of genetic variants in IGF genes modifies associations between indicators of energy balance and colorectal cancer risk. [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 2198. doi:10.1158/1538-7445.AM2014-2198