Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP

Timothy H T Cheng,Colon Cancer Family Registry ,Huw Thomas,Cgems ,Brian Saunders,Sue Clark,Lynn Martin,Graham Casey,Ian Tomlinson,Ella Barclay,Maggie Gorman

doi:10.1038/ejhg.2014.74

Abstract

The presence of multiple (5–100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P=5.7 × 10−7). The association was stronger in those with ≥10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have ‘polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients.

Highlights

Most colorectal cancers (CRCs) probably arise from adenomatous polyps
The position of the germline APC variants influences the ‘classical’ (4100 adenomas) familial adenomatous polyposis (FAP) phenotype: for example, severe colonic polyposis is associated with germline variants near codon 1309.5 several studies have addressed the possibility that modifier genes unlinked to APC influence the FAP phenotype.[6,7,8]
By testing individuals with small numbers of colorectal adenomas, but no history of CRC, we previously showed that some single-nucleotide polymorphisms (SNPs) predispose to CRC through the development of adenomas.[11]

Summary

Introduction

Most colorectal cancers (CRCs) probably arise from adenomatous polyps. There is a clinically important subset of patients who are found to have multiple (five or more) colorectal adenomas, a phenotype that is suggestive of an inherited genetic predisposition. FAP, MAP and PPAP had been excluded in each case using direct sequencing of (i) the regions of APC associated with attenuated disease (and the entire gene for those with close to 100 adenomas), (ii) the common northern European MUTYH variants p.Tyr179Cys and p.Gly396Asp[12] and (iii) the exonuclease domains of POLE and POLD1.3 One hundred and forty-two patients (79 families) with FAP and pathogenic germline APC variants were studied, as were 30 cases with a classical FAP phenotype and no identified disease-causing variant in APC, MUYTH, POLE or POLD1.

Results

Conclusion