Meta-analysis of new genome-wide association studies of colorectal cancer risk.

Author(s): Peters U,  Hutter CM,  Hsu L,  Schumacher FR,  Conti DV,  Carlson CS,  Edlund CK,  Haile RW,  Gallinger S,  Zanke BW,  Lemire M,  Rangrej J,  Vijayaraghavan R,  Chan AT,  Hazra A,  Hunter DJ,  Ma J,  Fuchs CS,  Giovannucci EL,  Kraft P,  Liu Y,  Chen L,  Jiao S,  Makar KW,  Taverna D,  Gruber SB,  Rennert G,  Moreno V,  Ulrich CM,  Woods MO,  Green RC,  Parfrey PS,  Prentice RL,  Kooperberg C,  Jackson RD,  Lacroix AZ,  Caan BJ,  Hayes RB,  Berndt SI,  Chanock SJ,  Schoen RE,  Chang-Claude J,  Hoffmeister M,  Brenner H,  Frank B,  Bézieau S,  Küry S,  Slattery ML,  Hopper JL,  Jenkins MA,  Le Marchand L,  Lindor NM,  Newcomb PA,  Seminara D,  Hudson TJ,  Duggan DJ,  Potter JD,  Casey G

Journal: Hum Genet

Date: 2012 Feb

Major Program(s) or Research Group(s): EDRG, PLCO

PubMed ID: 21761138

PMC ID: PMC3257356

Abstract: Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for GWAS of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios and 95% confidence intervals using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using ten independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured ten SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p value range 0.02 to 1.8 × 10(-8)). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p < 0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p value 0.03; combined p value 7.3 × 10(-5)). In a region on 5p33.15, which includes the coding regions of the TERT-CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant association with rs2853668 (replication p value 0.03; combined p value 1.9 × 10(-4)). Our study suggests a complex nature of the contribution of common genetic variants to risk for colorectal cancer.