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PURPOSE: Identification of single-nucleotide polymorphisms (SNP) 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 postpolypectomy disease recurrence. Genome-wide significance was defined as false discovery rate less than 0.05, unadjusted P = 7.4 × 10(-7). Validation phase: results were further evaluated using 4,175 familial colorectal adenoma cases and 5,036 controls from patients of European ancestry [COloRectal Gene Identification consortium (CORGI), 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 OR > 2). Five variants in strong pairwise linkage disequilibrium (rs7278863, rs2837237, rs741864, rs741864, and rs2837241; r(2) = 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 (CI), 1.50-2.91], also predicted colorectal cancer development in a validation analysis (P = 0.019) using a series of adenoma cases or colorectal cancer (CORGI study) and 3 sets of colorectal cancer 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 colorectal cancer. The variant at rs1535989 may identify patients whose risk for neoplasia warrants increased colonoscopic surveillance.

Original publication

DOI

10.1158/1078-0432.CCR-13-0550

Type

Journal article

Journal

Clin Cancer Res

Publication Date

01/12/2013

Volume

19

Pages

6430 - 6437

Keywords

Adenoma, Anticarcinogenic Agents, Case-Control Studies, Celecoxib, Colorectal Neoplasms, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Genome-Wide Association Study, Germ-Line Mutation, Humans, Linkage Disequilibrium, Male, Neoplasm Recurrence, Local, Polymorphism, Single Nucleotide, Prospective Studies, Pyrazoles, Randomized Controlled Trials as Topic, Sulfonamides