title: Chromosome 8q23.3 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome.
abstract: OBJECTIVE
  Recent genome-wide association studies have identified common low-risk variants for colorectal cancer (CRC). To assess whether these influence CRC risk in the Lynch syndrome, we genotyped these variants in a large series of proven mutation carriers.
  
  
  METHODS
  We studied 675 individuals from 127 different families from the Dutch Lynch syndrome Registry whose mutation carrier status was known. We genotyped 8q24.21, 8q23.3, 10p14, 11q23.1, 15q13.3, and 18q21.1 variants in carriers of a mismatch repair gene mutation. Univariate and multivariate analysis was used to analyse the association between the presence of a risk variant and CRC risk.
  
  
  RESULTS
  A significant association was found between CRC risk and rs16892766 (8q23.3) and rs3802842 (11q23.1). For rs16892766, possession of the C-allele was associated with an elevated risk of CRC in a dose-dependent fashion, with homozygosity for CC being associated with a 2.16-fold increased risk. For rs3802842, the increased risk of CRC associated with the C-allele was only found among female carriers, while CRC risk was substantially higher among homozygous (hazard ratio [HR] 3.08) than among heterozygous carriers of the C-allele (HR 1.49). In an additive model of both variants, the risk was significantly associated with the number of risk alleles (HR 1.60 for carriers of 2 or more risk alleles). The effects were stronger in female carriers than in male carriers.
  
  
  CONCLUSIONS
  We have identified 2 loci that are significantly associated with CRC risk in Lynch syndrome families. These modifiers may be helpful in identifying high-risk individuals who require more intensive surveillance.
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, The Netherlands.
authors.forename: Juul T
authors.initials: JT
authors.lastname: Wijnen
authors.forename: Richard M
authors.initials: RM
authors.lastname: Brohet
authors.forename: Ronald
authors.initials: R
authors.lastname: van Eijk
authors.forename: Shanty
authors.initials: S
authors.lastname: Jagmohan-Changur
authors.forename: Anneke
authors.initials: A
authors.lastname: Middeldorp
authors.forename: Carli M
authors.initials: CM
authors.lastname: Tops
authors.forename: Mario
authors.initials: M
authors.lastname: van Puijenbroek
authors.forename: Margreet G E M
authors.initials: MG
authors.lastname: Ausems
authors.forename: Encarna
authors.initials: E
authors.lastname: Gómez García
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: Hes
authors.forename: Nicoline
authors.initials: N
authors.lastname: Hoogerbrugge
authors.forename: Fred H
authors.initials: FH
authors.lastname: Menko
authors.forename: Theo A M
authors.initials: TA
authors.lastname: van Os
authors.forename: Rolf H
authors.initials: RH
authors.lastname: Sijmons
authors.forename: Senno
authors.initials: S
authors.lastname: Verhoef
authors.forename: Anja
authors.initials: A
authors.lastname: Wagner
authors.forename: Fokko M
authors.initials: FM
authors.lastname: Nagengast
authors.forename: Jan H
authors.initials: JH
authors.lastname: Kleibeuker
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.forename: David
authors.initials: D
authors.lastname: Goldgar
authors.forename: Ian P
authors.initials: IP
authors.lastname: Tomlinson
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.forename: Tom
authors.initials: T
authors.lastname: van Wezel
authors.forename: Hans F A
authors.initials: HF
authors.lastname: Vasen
mesh_terms: D000328:Adult; D000368:Aged; D002880:Chromosomes, Human, Pair 11; D002898:Chromosomes, Human, Pair 8; D015179:Colorectal Neoplasms / Q000209:etiology*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D053843:DNA Mismatch Repair; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide