Abstract
BackgroundCommon single-nucleotide polymorphisms (SNPs) in ten chromosomal loci have been shown to predispose to colorectal cancer (CRC) in genome-wide association studies. A plausible biological mechanism of CRC susceptibility associated with genetic variation has so far only been proposed for three loci, each pointing to variants that affect gene expression through distant regulatory elements. In this study, we aimed to gain insight into the molecular basis of seven low-penetrance CRC loci tagged by rs4779584 at 15q13, rs10795668 at 10p14, rs3802842 at 11q23, rs4444235 at 14q22, rs9929218 at 16q22, rs10411210 at 19q13, and rs961253 at 20p12.MethodsPossible somatic gain of the risk allele or loss of the protective allele was studied by analyzing allelic imbalance in tumour and corresponding normal tissue samples of heterozygous patients. Functional variants were searched from in silico predicted enhancer elements locating inside the CRC-associating linkage-disequilibrium regions.ResultsNo allelic imbalance targeting the SNPs was observed at any of the seven loci. Altogether, 12 SNPs that were predicted to disrupt potential transcription factor binding sequences were genotyped in the same population-based case-control series as the seven tagging SNPs originally. None showed association with CRC.ConclusionsThe results of the allelic imbalance analysis suggest that the seven CRC risk variants are not somatically selected for in the neoplastic progression. The bioinformatic approach was unable to pinpoint cancer-causing variants at any of the seven loci. While it is possible that many of the predisposition loci for CRC are involved in control of gene expression by targeting transcription factor binding sites, also other possibilities, such as regulatory RNAs, should be considered.
Highlights
Common single-nucleotide polymorphisms (SNPs) in ten chromosomal loci have been shown to predispose to colorectal cancer (CRC) in genome-wide association studies
Each of the ten loci independently predispose to CRC with allelic odds ratios (ORs) of
We have previously demonstrated that the tag SNP rs6983267 at 8q24 directly disrupts a TCF-4 transcription factor binding site and enhances Wnt signalling in the colon [11]
Summary
Common single-nucleotide polymorphisms (SNPs) in ten chromosomal loci have been shown to predispose to colorectal cancer (CRC) in genome-wide association studies. Ten chromosomal loci have far been shown to modestly increase colorectal cancer (CRC) risk, based on genome-wide association studies (GWASs) [1,2,3,4,5,6,7,8,9]. We have previously demonstrated that the tag SNP rs6983267 at 8q24 directly disrupts a TCF-4 transcription factor binding site and enhances Wnt signalling in the colon [11] This was supported by a simultaneous study showing a physical interaction between rs6983267 region and MYC proto-oncogene [12]. Based on the genes that locate inside or near the CRC-associating regions, including GREM1 at 15q13 and BMP4 at 14q22, alterations in TGFb-superfamily signalling appear to be at the basis of several loci [10]
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