Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer.

Whilst common genetic variation in many non-coding genomic regulatory regions are known to impart risk of colorectal cancer (CRC), much of the heritability of CRC remains unexplained. To examine the role of recurrent coding sequence variation in CRC aetiology, we genotyped 12,638 CRCs cases and 29,045 controls from six European populations. Single-variant analysis identified a coding variant (rs3184504) in SH2B3 (12q24) associated with CRC risk (OR = 1.

Reduced type II interleukin-4 receptor signalling drives initiation, but not progression, of colorectal carcinogenesis: evidence from transgenic mouse models and human case-control epidemiological observations.

We investigated the role of interleukin (IL)-4 receptor (IL-4R) signalling during mouse carcinogen-induced colorectal carcinogenesis and in a case-control genetic epidemiological study of IL-4Rα single nucleotide polymorphisms (SNPs). Azoxymethane-induced aberrant crypt focus (ACF; 6 weeks) and tumours (32 weeks) were analysed in wild-type (WT) BALB/c mice, as well as in IL-4Rα (-) (/-) , IL-13 (-/-) and 'double-knockout' (DKO) animals. Colorectal cancer (CRC) cases (1502) and controls (584) were genotyped for six coding IL-4Rα SNPs.

Polymorphisms in xenobiotic metabolizing enzymes and diet influence colorectal adenoma risk.

Objectives: We have earlier shown that diet and xenobiotic metabolizing enzyme genotypes influence colorectal cancer risk, and now investigate whether similar associations are seen in patients with premalignant colorectal adenomas (CRA), recruited during the pilot phase of the Scottish Bowel Screening Programme.

Methods: Nineteen polymorphisms in 13 genes [cytochrome P450 (P450), glutathione S-transferase (GST), N-acetyl transferase, quinone reductase (NQ01) and microsomal epoxide hydrolase (EPHX1) genes] were genotyped using multiplex PCR or Taqman-based allelic discrimination assays and analyzed in conjunction with diet, assessed by food frequency questionnaire, in a case-control study [317 CRA cases (308 cases genotyped), 296 controls]. Findings significant at a nominal 5% level are reported.

Methylene tetrahydrofolate reductase genotype modifies the chemopreventive effect of folate in colorectal adenoma, but not colorectal cancer.

Epidemiologic evidence suggests a role for folate, a critical component of the 1-carbon cycle, in colorectal adenoma and cancer pathogenesis. Low folate levels, along with genetic polymorphisms in key enzymes such as methylene tetrahydrofolate reductase (MTHFR), can cause DNA hypomethylation and aberrant CpG methylation, which have been associated with colorectal tumor development. We investigated self-reported folate and alcohol intake alongside possible modifying effects of MTHFR 677 C>T and 1298 A>C polymorphisms in UK case-control studies of colorectal adenoma (317 cases, 296 controls) and cancer (500 cases, 742 controls).