Abstract

BackgroundThe genetics of sporadic and non-syndromic familial colorectal cancer (CRC) is not well defined. However, genetic factors that promote the development of precursor lesions, i.e. adenomas, might also predispose to CRC. Recently, an association of colorectal adenoma with two variants (c.507C>T;p.L169L and c.511G>T;p.A171S) of the ileal sodium dependent bile acid transporter gene (SLC10A2) has been reported. Here, we reconstructed haplotypes of the SLC10A2 gene locus and tested for association with non-syndromic familial and sporadic CRC compared to 'hyper-normal' controls who displayed no colorectal polyps on screening colonoscopy.MethodsWe included 150 patients with sporadic CRC, 93 patients with familial CRC but exclusion of familial adenomatous polyposis and Lynch's syndrome, and 204 'hyper-normal' controls. Haplotype-tagging SLC10A2 gene variants were identified in the Hapmap database and genotyped using PCR-based 5' exonuclease assays with fluorescent dye-labelled probes. Haplotypes were reconstructed using the PHASE algorithm. Association testing was performed with both SNPs and reconstructed haplotypes.ResultsMinor allele frequencies of all SLC10A2 polymorphisms are within previously reported ranges, and no deviations from Hardy-Weinberg equilibrium are observed. However, we found no association with any of the SLC10A2 haplotypes with sporadic or familial CRC in our samples (all P values > 0.05).ConclusionCommon variants of the SLC10A2 gene are not associated with sporadic or familial CRC. Hence, albeit this gene might be associated with early stages of colorectal neoplasia, it appears not to represent a major risk factor for progression to CRC.

Highlights

  • The genetics of sporadic and non-syndromic familial colorectal cancer (CRC) is not well defined

  • For the present study we chose to compare the effect of genetic variants in (i) familial CRC cases and (ii) sporadic CRC patients without a personal or familial history of CRC to a 'hyper-normal' control group with no signs of adenomas or cancer on screening colonoscopy and no personal or familial history of CRC

  • 'Hypernormal' controls were age-matched to sporadic CRC patients to reduce the possibility of inclusion of patients who might develop colorectal adenomas or CRC in later life

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Summary

Introduction

The genetics of sporadic and non-syndromic familial colorectal cancer (CRC) is not well defined. We reconstructed haplotypes of the SLC10A2 gene locus and tested for association with non-syndromic familial and sporadic CRC compared to 'hypernormal' controls who displayed no colorectal polyps on screening colonoscopy. The effect of each variable may vary considerably, ranging from monogenic familial cancer syndromes that are predominantly caused by genetic defects to sporadic CRCs, which are probably due to life-long exposure to environmental factors with only minor effects of genetic predisposition. For the present study we chose to compare the effect of genetic variants in (i) familial CRC cases (after exclusion of Lynch's syndrome and familial adenomatous polyposis [FAP]) and (ii) sporadic CRC patients without a personal or familial history of CRC to a 'hyper-normal' control group with no signs of adenomas or cancer on screening colonoscopy and no personal or familial history of CRC

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