title: High risk of colorectal and endometrial cancer in Ashkenazi families with the MSH2 A636P founder mutation.
abstract: OBJECTIVE
  The MSH2 A636P mutation is a founder mutation in Ashkenazi Jews that causes Lynch syndrome, with a prevalence of 0.4%-0.7%. Estimates of age-specific cumulative risk and lifetime risk for colorectal cancer (CRC) and endometrial cancer (EC) specific to carriers of this mutation are not available.
  
  
  METHODS
  We studied 27 families with MSH2 A636P gene mutations identified in Israel; 13 were identified via a population-based, case-control study and 14 were identified from a clinical genetics service. Age-specific cumulative risks (penetrance) and hazard ratio (HR) estimates of CRC and EC risks were calculated and compared with the general Ashkenazi population using modified segregation analysis. An ascertainment-corrected likelihood that combined population-based and clinic-based sampling provided a powerful analysis for estimating penetrance. We analyzed 74 cases of CRC (40 in the clinic series and 34 in the population-based series), diagnosed at median ages of 50 years (men) and 49 years (women) in the combined sample.
  
  
  RESULTS
  The cumulative risk of CRC at age 70 was 61.62% for men (95% confidence interval [CI], 37.49%-76.45%) and 61.08% for women (95% CI, 39.39%-75.14%), with overall HRs of 31.8 (19.9-51.0) and 41.8 (27.4-64.0), respectively. There were 28 cases of EC, diagnosed at a median age of 53.0 years. The cumulative risk of EC was 55.64% (95% CI, 33.07%-70.58%) with an overall HR of 66.7 (41.7-106.7).
  
  
  CONCLUSIONS
  Lifetime risks of CRC and EC in MSH2 A636P carriers are high even after adjusting for ascertainment. These estimates are valuable for patients and providers; specialized cancer screening is necessary for carriers of this mutation.
authors.affiliation: Department of Biostatistics, University of Michigan Medical School, Ann Arbor, Michigan 48105, USA.
authors.forename: Bhramar
authors.initials: B
authors.lastname: Mukherjee
authors.forename: Gad
authors.initials: G
authors.lastname: Rennert
authors.forename: Jaeil
authors.initials: J
authors.lastname: Ahn
authors.forename: Sara
authors.initials: S
authors.lastname: Dishon
authors.forename: Flavio
authors.initials: F
authors.lastname: Lejbkowicz
authors.forename: Hedy S
authors.initials: HS
authors.lastname: Rennert
authors.forename: Stacey
authors.initials: S
authors.lastname: Shiovitz
authors.forename: Victor
authors.initials: V
authors.lastname: Moreno
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000175:diagnosis / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D040941:Heredity; D006801:Humans; D007557:Israel / Q000453:epidemiology; D007585:Jews / Q000235:genetics*; D016013:Likelihood Functions; D008297:Male; D008403:Mass Screening / Q000379:methods; D008875:Middle Aged; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D016016:Proportional Hazards Models; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D055815:Young Adult
chemical_list: C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein