title: Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study.
abstract: OBJECTIVE
  The MutY human homologue (MYH) gene is a member of the base-excision repair pathway involved in the repair of oxidative DNA damage. The objective of this study was to determine colorectal cancer (CRC) risk associated with mutations in the MYH gene.
  
  
  METHODS
  A total of 3811 CRC cases and 2802 controls collected from a multisite CRC registry were screened for 9 germline MYH mutations; subjects with any mutation underwent screening of the entire MYH gene. Logistic regression was used to estimate age- and sex-adjusted odds ratios (AOR). Clinicopathologic and epidemiologic data were reviewed to describe the phenotype associated with MYH mutation status and assess for potential confounding and effect modification.
  
  
  RESULTS
  Twenty-seven cases and 1 control subject carried homozygous or compound heterozygous MYH mutations (AOR, 18.1; 95% confidence interval, 2.5-132.7). CRC cases with homozygous/compound heterozygous mutations were younger at diagnosis (P=.01), had a higher proportion of right-sided (P=.01), synchronous cancers (P<.01), and personal history of adenomatous polyps (P=.003). Heterozygous MYH mutations were identified in 87 CRC cases and 43 controls; carriers were at increased risk of CRC (AOR, 1.48; 95% confidence interval, 1.02-2.16). There was a higher prevalence of low-frequency microsatellite instability (MSI) in tumors from heterozygous and homozygous/compound heterozygous MYH mutation carriers (P=.02); MSI status modified the CRC risk associated with heterozygous MYH mutations (P interaction<.001).
  
  
  CONCLUSIONS
  Homozygous/compound heterozygous MYH mutations account for less than 1% of CRC cases. Heterozygous carriers are at increased risk of CRC. Further studies are needed to understand the possible interaction between the base excision repair and low-frequency MSI pathways.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Cleary
authors.forename: Michelle
authors.initials: M
authors.lastname: Cotterchio
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: Hyeja
authors.initials: H
authors.lastname: Kim
authors.forename: Robert
authors.initials: R
authors.lastname: Bristow
authors.forename: Roger
authors.initials: R
authors.lastname: Green
authors.forename: Robert
authors.initials: R
authors.lastname: Haile
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Loic
authors.initials: L
authors.lastname: LeMarchand
authors.forename: Noralane
authors.initials: N
authors.lastname: Lindor
authors.forename: Patrick
authors.initials: P
authors.lastname: Parfrey
authors.forename: John
authors.initials: J
authors.lastname: Potter
authors.forename: Ban
authors.initials: B
authors.lastname: Younghusband
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D002170:Canada; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D016015:Logistic Models; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D012307:Risk Factors; D014481:United States
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase