TY - JOUR
T1 - Germline Variants and Advanced Colorectal Adenomas
T2 - Adenoma Prevention with Celecoxib Trial Genome-wide Association Study
AU - APC Trial Collaborators
AU - Wang, Jiping
AU - Carvajal-Carmona, Luis G
AU - Chu, Jen-Hwa
AU - Zauber, Ann G
AU - Kubo, Michikai
AU - Matsuda, Koichi
AU - Dunlop, Malcolm
AU - Houlston, Richard S
AU - Sieber, Oliver
AU - Lipton, Lara
AU - Gibbs, Peter
AU - Martin, Nicholas G
AU - Montgomery, Grant W
AU - Young, Joanne
AU - Baird, Paul N
AU - Ratain, Mark J
AU - Nakamura, Yusuke
AU - Weiss, Scott T
AU - Tomlinson, Ian
AU - Bertagnolli, Monica M
N1 - M. Dunlop received from the Medical Research Council (G0000657-53203), CORE and Scottish Executive Chief Scientist's Office (K/OPR/2/2/D333, CZB/4/449).
PY - 2013/12/1
Y1 - 2013/12/1
N2 - 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 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. Clin Cancer Res; 1-8. ©2013 AACR.
AB - 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 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. Clin Cancer Res; 1-8. ©2013 AACR.
U2 - 10.1158/1078-0432.CCR-13-0550
DO - 10.1158/1078-0432.CCR-13-0550
M3 - Article
C2 - 24084763
SN - 1078-0432
VL - 19
SP - 6430
EP - 6437
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -