title: Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP.
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.
authors.affiliation: Molecular and Population Genetics Laboratory, Nuffield Department of Clinical Medicine, Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors.forename: Timothy H T
authors.initials: TH
authors.lastname: Cheng
authors.affiliation: Molecular and Population Genetics Laboratory, Nuffield Department of Clinical Medicine, Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors.forename: Maggie
authors.initials: M
authors.lastname: Gorman
authors.affiliation: Molecular and Population Genetics Laboratory, Nuffield Department of Clinical Medicine, Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors.forename: Lynn
authors.identifier: 000000033962389X
authors.initials: L
authors.lastname: Martin
authors.affiliation: Molecular and Population Genetics Laboratory, Nuffield Department of Clinical Medicine, Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors.forename: Ella
authors.initials: E
authors.lastname: Barclay
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA.
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.affiliation: Wolfson Unit for Endoscopy, Imperial College School of Medicine, St Mark's Hospital, Harrow, UK.
authors.forename: Brian
authors.initials: B
authors.lastname: Saunders
authors.affiliation: Family Cancer Registry, Imperial College School of Medicine, St Mark's Hospital, Harrow, UK.
authors.forename: Huw
authors.initials: H
authors.lastname: Thomas
authors.affiliation: Polyposis Registry, Imperial College School of Medicine, St Mark's Hospital, Harrow, UK.
authors.forename: Sue
authors.initials: S
authors.lastname: Clark
authors.affiliation: 1] Molecular and Population Genetics Laboratory, Nuffield Department of Clinical Medicine, Wellcome Trust Centre for Human Genetics, Oxford, UK [2] Oxford NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors.forename: Ian
authors.identifier: 0000000330371470
authors.initials: I
authors.lastname: Tomlinson
mesh_terms: D000236:Adenoma / Q000175:diagnosis / Q000235:genetics*; D011125:Adenomatous Polyposis Coli / Q000175:diagnosis / Q000235:genetics*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000368:Aged; D000483:Alleles; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics; D005260:Female; D060045:Genes, Modifier; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase