title: Colorectal cancer risk variants on 11q23 and 15q13 are associated with unexplained adenomatous polyposis.
abstract: BACKGROUND
  Colorectal adenomatous polyposis is associated with a high risk of colorectal cancer (CRC) and is frequently caused by germline mutations in APC or MUTYH. However, in about 20-30% of patients no underlying gene defect can be identified. In this study, we tested if recently identified CRC risk variants play a role in patients with >10 adenomas.
  
  
  METHODS
  We analysed a total of 16 SNPs with a reported association with CRC in a cohort of 252 genetically unexplained index patients with >10 colorectal adenomas and 745 controls. In addition, we collected detailed clinical information from index patients and their first-degree relatives (FDRs).
  
  
  RESULTS
  We found a statistically significant association with two of the variants tested: rs3802842 (at chromosome 11q23, OR=1.60, 95% CI 1.3 to 2.0) and rs4779584 (at chromosome 15q13, OR=1.50, 95% CI 1.2 to 1.9). The majority of index patients (84%) had between 10 and 100 adenomas and 15% had >100 adenomas. Only two index patients (1%), both with >100 adenomas, had FDRs with polyposis. Forty-one per cent of the index patients had one or more FDRs with CRC.
  
  
  CONCLUSIONS
  These SNPs are the first common, low-penetrant variants reported to be associated with adenomatous polyposis not caused by a defect in the APC, MUTYH, POLD1 and POLE genes. Even though familial occurrence of polyposis was very rare, CRC was over-represented in FDRs of polyposis patients and, if confirmed, these relatives will therefore benefit from surveillance.
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: Hes
authors.forename: Dina
authors.initials: D
authors.lastname: Ruano
authors.forename: Marry
authors.initials: M
authors.lastname: Nieuwenhuis
authors.forename: Carli M
authors.initials: CM
authors.lastname: Tops
authors.forename: Melanie
authors.initials: M
authors.lastname: Schrumpf
authors.forename: Maartje
authors.initials: M
authors.lastname: Nielsen
authors.forename: Petra E A
authors.initials: PE
authors.lastname: Huijts
authors.forename: Juul T
authors.initials: JT
authors.lastname: Wijnen
authors.forename: Anja
authors.initials: A
authors.lastname: Wagner
authors.forename: Encarna B
authors.initials: EB
authors.lastname: Gómez García
authors.forename: Rolf H
authors.initials: RH
authors.lastname: Sijmons
authors.forename: Fred H
authors.initials: FH
authors.lastname: Menko
authors.forename: Tom G W
authors.initials: TG
authors.lastname: Letteboer
authors.forename: Nicoline
authors.initials: N
authors.lastname: Hoogerbrugge
authors.forename: Jan
authors.initials: J
authors.lastname: Harryvan
authors.forename: Ellen
authors.initials: E
authors.lastname: Kampman
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.forename: Hans F A
authors.initials: HF
authors.lastname: Vasen
authors.forename: Tom
authors.initials: T
authors.lastname: van Wezel
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000150:complications* / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D002869:Chromosome Aberrations; D002880:Chromosomes, Human, Pair 11; D002884:Chromosomes, Human, Pair 15; D015179:Colorectal Neoplasms / Q000150:complications* / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D055815:Young Adult
keywords: Cancer: colon; Clinical genetics; Genetic screening/counselling