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

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

doi:10.1038/ejhg.2014.74

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

Journal article

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

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

European journal of human genetics : EJHG, Vol.23(2), pp.260-263

02/2015

DOI: 10.1038/ejhg.2014.74

PMCID: PMC4140766

PMID: 24801760

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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.

Phenotype

Adenomatous Polyposis Coli Protein - genetics

Adenoma - diagnosis

Genetic Predisposition to Disease

Adenoma - genetics

Colorectal Neoplasms - genetics

Humans

Middle Aged

DNA Glycosylases - genetics

Male

Colorectal Neoplasms - diagnosis

Alleles

Germ-Line Mutation

Female

Aged

Polymorphism, Single Nucleotide

Genes, Modifier

Adenomatous Polyposis Coli - genetics

Adenomatous Polyposis Coli - diagnosis

Details

Title: Subtitle: Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP
Creators: Timothy H T Cheng - Molecular and Population Genetics Laboratory, Nuffield Department of Clinical Medicine, Wellcome Trust Centre for Human Genetics, Oxford, UK
Maggie Gorman - Molecular and Population Genetics Laboratory, Nuffield Department of Clinical Medicine, Wellcome Trust Centre for Human Genetics, Oxford, UK
Lynn Martin - Molecular and Population Genetics Laboratory, Nuffield Department of Clinical Medicine, Wellcome Trust Centre for Human Genetics, Oxford, UK
Ella Barclay - Molecular and Population Genetics Laboratory, Nuffield Department of Clinical Medicine, Wellcome Trust Centre for Human Genetics, Oxford, UK
Graham Casey - Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA
Colon Cancer Family Registry
Brian Saunders - Wolfson Unit for Endoscopy, Imperial College School of Medicine, St Mark's Hospital, Harrow, UK
Huw Thomas - Family Cancer Registry, Imperial College School of Medicine, St Mark's Hospital, Harrow, UK
Sue Clark - Polyposis Registry, Imperial College School of Medicine, St Mark's Hospital, Harrow, UK
Ian Tomlinson - 1] Molecular and Population Genetics Laboratory, Nuffield Department of Clinical Medicine, Wellcome Trust Centre for Human Genetics, Oxford, UK Oxford NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Oxford, UK
Contributors: Jesus Gonzalez Bosquet (Contributor) - University of Iowa, Obstetrics and Gynecology
Resource Type: Journal article
Publication Details: European journal of human genetics : EJHG, Vol.23(2), pp.260-263
Publisher: England
DOI: 10.1038/ejhg.2014.74
PMID: 24801760
PMCID: PMC4140766
ISSN: 1018-4813
eISSN: 1476-5438
Grant note: U24 CA074794 / NCI NIH HHS G0401527 / Medical Research Council U24 CA097735 / NCI NIH HHS U01 CA097735 / NCI NIH HHS U01 CA074800 / NCI NIH HHS U01 CA074783 / NCI NIH HHS U24 CA074783 / NCI NIH HHS U01 CA074794 / NCI NIH HHS 090532 / Wellcome Trust UM1 CA167551 / NCI NIH HHS U01 CA074799 / NCI NIH HHS Cancer Research UK 14136 / Cancer Research UK U24 CA074800 / NCI NIH HHS 10124 / Cancer Research UK G1000143 / Medical Research Council 084818 / Wellcome Trust U24 CA074799 / NCI NIH HHS 090532/Z/09/Z / Wellcome Trust
Language: English
Date published: 02/2015
Academic Unit: Obstetrics and Gynecology
Record Identifier: 9983931810602771

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