Germline variants and advanced colorectal adenomas: Adenoma Prevention with Celecoxib trial genome-wide association study

Purpose: Identification of single nucleotide polymorphisms (SNPs) associated with development of advanced colorectal adenomas. Experimental Design: Discovery Phase: 1,406 Caucasian patients (139 advanced adenoma cases and 1,267 controls) from the Adenoma Prevention with Celecoxib (APC) trial were included in a genome-wide association study (GWAS) to identify variants associated with post-polypectomy disease recurrence. Genome-wide significance was defined as false discovery rate < 0.05, unadjusted p=7.4×10−7. Validation Phase: Results were further evaluated using 4,175 familial colorectal adenoma or CRC cases and 5,036 controls from patients of European ancestry (COloRectal Gene Identification consortium, Scotland, Australia and VQ58). Results: Our study identified eight SNPs associated with advanced adenoma risk in the APC trial (rs2837156, rs7278863, rs2837237, rs2837241, rs2837254, rs741864 at 21q22.2, and rs1381392 and rs17651822 at 3p24.1, at p<10–7 level with odds ratio – OR>2). Five variants in strong pairwise linkage disequilbrium (rs7278863, rs2837237, rs741864, rs741864 and rs2837241, r2=0.8–1) are in or near the coding region for the tight junction adhesion protein, IGSF5. An additional variant associated with advanced adenomas, rs1535989 (minor allele frequency 0.11; OR 2.09; 95% confidence interval 1.50–2.91), also predicted CRC development in a validation analysis (p=0.019) using a series of adenoma cases or CRC (CORGI study) and 3 sets of CRC cases and controls (Scotland, VQ58 and Australia, N=9,211). Conclusions: Our results suggest that common polymorphisms contribute to the risk of developing advanced adenomas and might also contribute to the risk of developing CRC. The variant at rs1535989 may identify patients whose risk for neoplasia warrants increased colonoscopic surveillance.