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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.

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly influence the risk of developing colorectal cancer (CRC). To enhance power to identify additional loci with similar effect sizes, we conducted a meta-analysis of two GWA studies, comprising 13,315 individuals genotyped for 38,710 common tagging SNPs. We undertook replication testing in up to eight independent case-control series comprising 27,418 subjects. We identified four previously unreported CRC risk loci at 14q22.2 (rs4444235, BMP4; P = 8.1 × 10 −10 ), 16q22.1 (rs9929218, CDH1; P = 1.2 × 10 −8 ), 19q13.1 (rs10411210, RHPN2; P = 4.6 × 10 −9 ) and 20p12.3 (rs961253; P = 2.0 × 10 −10 ). These findings underscore the value of large sample series for discovery and follow-up of genetic variants contributing to the etiology of CRC.Whereas inherited susceptibility is responsible for ~35% of all CRC 1 , high-risk germline mutations in APC, the mismatch repair (MMR) genes, MUTYH (MYH), SMAD4, BMPR1A and STK11/LKB1 account for <6% of all cases 2 . Recent GWA studies have validated the hypothesis that part of the heritable risk is caused by common, low-risk variants, identifying CRC susceptibility loci mapping to 8q24 (rs6983267) 3, 4, 8q23.3 (rs16892766, EIF3H)5, 10p14 (rs10795668)5, 11q23 (rs3802842)6, 15q13 (rs4779584)7 and 18q21 (rs4939827, SMAD7) 6,8 .GWA studies are not contingent on prior information concerning candidate genes or pathways, and thereby have the ability to identify important variants in hitherto unstudied genes. However, the effect sizes of individual variants, the need for stringent thresholds for establishing statistical significance, and financial constraints on numbers of variants that can be followed up inevitably constrain study power. We recently published two separate GWA studies for CRC. To augment the power to detect additional CRC risk loci, we have conducted a meta-analysis of data from these studies and followed up the best supported associations in large sample sets. This analysis, in conjunction with a replication study using eight independent case-control series, has enabled us to identify four new loci predisposing to CRC. This brings to ten the number of independent loci conclusively associated with CRC risk, and provides additional insight into the genetic architecture of inherited susceptibility to CRC. RESULTS Meta-analysis of genome-wide association scansThe GWA studies were both conducted by centers in London and Edinburgh, and were both based on designs involving two-phase strategies and using samples from UK populations NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2010 March 11. Published in final edited form as:Nat Genet. London phase 2 was based on genotyping 2,873 CRC cases and 2,871 controls ascertained through the National Study of Colorectal Cancer Genetics (NSCCG), whereas Edinburgh phase 2 was based on genotyping 2,057 cases and 2,111 controls. For phase 2, the London and Edinburgh samples were genotyped for a common s...

This is the first study to demonstrate a protective effect against CRC associated with the lowest dose of aspirin (75 mg per day) after only 5 years use in the general population. NSAID use prior to CRC diagnosis does not influence survival from the disease.

In vitro and in vivo laboratory data point to chemoprotective effects of flavonoids on colorectal cancer. However, there has been limited epidemiologic research on the dietary intake of flavonoids and risk of colorectal cancer. Recent expansions of dietary databases to include flavonoid data now make such studies feasible. Association between the six main classes of flavonoids and the risk of colorectal cancer was examined using data from a national prospective case-control study in Scotland, including 1,456 incident cases and 1,456 population-based controls matched on age, sex, and residence area. Dietary, including flavonoid data, were obtained from a validated, self-administered food frequency questionnaire. Risk of colorectal cancer was estimated using conditional logistic regression models in the whole sample and stratified by sex, smoking status, and cancer site and adjusted for established and putative risk factors. After energy adjustment, reductions in colorectal cancer risk associated with the highest quartiles of intake (versus the lowest quartile) were 27% for flavonols [odds ratio (OR), 0.73; P trend = 0.012], 32% for quercetin (OR, 0.68; P trend = 0.001), 32% for catechin (OR, 0.68; P trend < 0.0005); 26% for epicatechin (OR, 0.74; P trend = 0.019), and 22% for procyanidins (OR, 0.78; P trend = 0.031). The significant dose-dependent reductions in colorectal cancer risk that were associated with increased consumption of flavonols, quercetin, catechin, and epicatechin remained robust after controlling for overall fruit and vegetable consumption or for other flavonoid intake. The risk reductions were greater among nonsmokers, but no interaction beyond a multiplicative effect was present. Sex-specific or cancer-type differences were not observed. No risk reductions were associated with intake of flavones (P trend = 0.64), flavonones (P trend = 0.22), and phytoestrogens (P trend = 0.26). This was the first of several a priori hypotheses to be tested in this large study and showed strong and linear inverse associations of flavonoids with colorectal cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(4):684 -93)