title: Colorectal cancer risk variants at 8q23.3 and 11q23.1 are associated with disease phenotype in APC mutation carriers.
abstract: Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high risk of developing colorectal cancer (CRC). The severity of polyposis is correlated with the site of the APC mutation. However, there is also phenotypic variability within families with the same underlying APC mutation, suggesting that additional factors influence the severity of polyposis. Genome-wide association studies identified several single nucleotide polymorphisms (SNPs) that are associated with CRC. We assessed whether these SNPs are associated with polyp multiplicity in proven APC mutation carriers. Sixteen CRC-associated SNPs were analysed in a cohort of 419 APC germline mutation carriers from 182 families. Clinical data were retrieved from the Dutch Polyposis Registry. Allele frequencies of the SNPs were compared for patients with <100 colorectal adenomas versus patients with ≥100 adenomas, using generalized estimating equations with the APC genotype as a covariate. We found a trend of association of two of the tested SNPs with the ≥100 adenoma phenotype: the C alleles of rs16892766 at 8q23.3 (OR 1.71, 95 % CI 1.05-2.76, p = 0.03, dominant model) and rs3802842 at 11q23.1 (OR 1.51, 95 % CI 1.03-2.22, p = 0.04, dominant model). We identified two risk variants that are associated with a more severe phenotype in APC mutation carriers. These risk variants may partly explain the phenotypic variability in families with the same APC gene defect. Further studies with a larger sample size are recommended to evaluate and confirm the phenotypic effect of these SNPs in FAP.
authors.affiliation: Netherlands Foundation for the Detetion of Hereditary Tumors, Leiden, The Netherlands. z.ghorbanoghli@gmail.com.|Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Rijnsburgerweg 10, 2333 AA, Leiden, The Netherlands. z.ghorbanoghli@gmail.com.
authors.forename: Z
authors.initials: Z
authors.lastname: Ghorbanoghli
authors.affiliation: Netherlands Foundation for the Detetion of Hereditary Tumors, Leiden, The Netherlands.
authors.forename: M H
authors.initials: MH
authors.lastname: Nieuwenhuis
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Jagmohan-Changur
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: F J
authors.initials: FJ
authors.lastname: Hes
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: C M
authors.initials: CM
authors.lastname: Tops
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Wagner
authors.affiliation: Department of Clinical Genetics, Amsterdam Medical Centre, Amsterdam, The Netherlands.
authors.forename: C M
authors.initials: CM
authors.lastname: Aalfs
authors.affiliation: Family Cancer Clinic, the Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Verhoef
authors.affiliation: Department of Clinical Genetics, University of Maastricht, Maastricht, The Netherlands.
authors.forename: E B
authors.initials: EB
authors.lastname: Gómez García
authors.affiliation: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: R H
authors.initials: RH
authors.lastname: Sijmons
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: F H
authors.initials: FH
authors.lastname: Menko
authors.affiliation: Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: T G
authors.initials: TG
authors.lastname: Letteboer
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Hoogerbrugge
authors.affiliation: Departments of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: van Wezel
authors.affiliation: Netherlands Foundation for the Detetion of Hereditary Tumors, Leiden, The Netherlands.|Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Rijnsburgerweg 10, 2333 AA, Leiden, The Netherlands.
authors.forename: H F A
authors.initials: HF
authors.lastname: Vasen
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.|Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: J T
authors.initials: JT
authors.lastname: Wijnen
mesh_terms: D000236:Adenoma / Q000235:genetics; D011125:Adenomatous Polyposis Coli / Q000235:genetics; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000328:Adult; D002880:Chromosomes, Human, Pair 11; D002898:Chromosomes, Human, Pair 8; D015179:Colorectal Neoplasms / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein
keywords: Cancer genetics; Colonic adenomas; Familial adenomatous polyposis; Genetic polymorphisms