No abstract

We devised and validated a method of identifying patients with colorectal cancer who are carriers of mutations in DNA repair genes. Survival was similar among carriers and noncarriers.

To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall; P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall; P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.

Genome-wide association (GWA) studies have thus far identified 10 loci at which common variants influence the risk of developing colorectal cancer (CRC). To enhance power to identify additional loci, we conducted a meta-analysis of three GWA studies from the UK totalling 3,334 cases and 4,628 controls, followed by multiple validation analyses, involving a total of 18,095 CRC cases and 20,197 controls. We identified new associations at 4 CRC risk loci: 1q41 (rs6691170, OR=1.06, P=9.55x10-10; rs6687758, OR=1.09, P=2.27x10-9); 3q26.2 (rs10936599, OR=0.93, P=3.39x10-8); 12q13.13 (rs11169552, OR=0.92, P=1.89x10-10; rs7136702, OR=1.06, P=4.02=x10-8); and 20q13.33 (rs4925386, OR=0.93, P=1.89x10-10). As well as identifying multiple new CRC risk loci this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered.