title: Are the common genetic variants associated with colorectal cancer risk for DNA mismatch repair gene mutation carriers?
abstract: BACKGROUND
  Genome-wide association studies have identified at least 15 independent common genetic variants associated with colorectal cancer (CRC) risk. The aim of this study was to investigate whether 11 of these variants are associated with CRC risk for carriers of germline mutations in DNA mismatch repair (MMR) genes.
  
  
  METHODS
  A total of 927 MMR gene mutation carriers (360 MLH1, 442 MSH2, 85 MSH6 and 40 PMS2) from 315 families enrolled in the Colon Cancer Family Registry, were genotyped for the single nucleotide polymorphisms (SNPs): rs16892766 (8q23.3), rs6983267 (8q24.21), rs719725 (9p24), rs10795668 (10p14), rs3802842 (11q23.1), rs4444235 (14q22.2), rs4779584 (15q13.3), rs9929218 (16q22.1), rs4939827 (18q21.1), rs10411210 (19q13.1) and rs961253 (20p12.3). We used a weighted Cox regression to estimate CRC risk for homozygous and heterozygous carriers of the risk allele compared with homozygous non-carriers as well as for an additive per allele model (on the log scale).
  
  
  RESULTS
  Over a total of 40,978 person-years observation, 426 (46%) carriers were diagnosed with CRC at a mean age of 44.3 years. For all carriers combined, we found no evidence of an association between CRC risk and the total number of risk alleles (hazard ratio [HR] per risk allele=0.97, 95% confidence interval [CI]=0.88-1.07, p=0.52).
  
  
  CONCLUSIONS
  We found no evidence that the SNPs associated with CRC in the general population are modifiers of the risk for MMR gene mutation carriers overall, and therefore any evidence of proven clinical utility in Lynch syndrome.
authors: Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Parkville, Victoria, Australia.
authors: Aung Ko
authors: AK
authors: Win
authors: John L
authors: JL
authors: Hopper
authors: Daniel D
authors: DD
authors: Buchanan
authors: Joanne P
authors: JP
authors: Young
authors: Albert
authors: A
authors: Tenesa
authors: James G
authors: JG
authors: Dowty
authors: Graham G
authors: GG
authors: Giles
authors: Jack
authors: J
authors: Goldblatt
authors: Ingrid
authors: I
authors: Winship
authors: Alex
authors: A
authors: Boussioutas
authors: Graeme P
authors: GP
authors: Young
authors: Susan
authors: S
authors: Parry
authors: John A
authors: JA
authors: Baron
authors: David
authors: D
authors: Duggan
authors: Steven
authors: S
authors: Gallinger
authors: Polly A
authors: PA
authors: Newcomb
authors: Robert W
authors: RW
authors: Haile
authors: Loïc
authors: L
authors: Le Marchand
authors: Noralane M
authors: NM
authors: Lindor
authors: Mark A
authors: MA
authors: Jenkins
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000235:genetics; D000328:Adult; D000483:Alleles; D015179:Colorectal Neoplasms / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D018570:Risk Assessment / Q000706:statistics & numerical data; D012307:Risk Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes