title: Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study.
abstract: OBJECTIVE
  To determine whether cancer risks for carriers and noncarriers from families with a mismatch repair (MMR) gene mutation are increased above the risks of the general population.
  
  
  METHODS
  We prospectively followed a cohort of 446 unaffected carriers of an MMR gene mutation (MLH1, n = 161; MSH2, n = 222; MSH6, n = 47; and PMS2, n = 16) and 1,029 their unaffected relatives who did not carry a mutation every 5 years at recruitment centers of the Colon Cancer Family Registry. For comparison of cancer risk with the general population, we estimated country-, age-, and sex-specific standardized incidence ratios (SIRs) of cancer for carriers and noncarriers.
  
  
  RESULTS
  Over a median follow-up of 5 years, mutation carriers had an increased risk of colorectal cancer (CRC; SIR, 20.48; 95% CI, 11.71 to 33.27; P < .001), endometrial cancer (SIR, 30.62; 95% CI, 11.24 to 66.64; P < .001), ovarian cancer (SIR, 18.81; 95% CI, 3.88 to 54.95; P < .001), renal cancer (SIR, 11.22; 95% CI, 2.31 to 32.79; P < .001), pancreatic cancer (SIR, 10.68; 95% CI, 2.68 to 47.70; P = .001), gastric cancer (SIR, 9.78; 95% CI, 1.18 to 35.30; P = .009), urinary bladder cancer (SIR, 9.51; 95% CI, 1.15 to 34.37; P = .009), and female breast cancer (SIR, 3.95; 95% CI, 1.59 to 8.13; P = .001). We found no evidence of their noncarrier relatives having an increased risk of any cancer, including CRC (SIR, 1.02; 95% CI, 0.33 to 2.39; P = .97).
  
  
  CONCLUSIONS
  We confirmed that carriers of an MMR gene mutation were at increased risk of a wide variety of cancers, including some cancers not previously recognized as being a result of MMR mutations, and found no evidence of an increased risk of cancer for their noncarrier relatives.
authors.affiliation: The University of Melbourne, Australia.
authors.forename: Aung Ko
authors.initials: AK
authors.lastname: Win
authors.forename: Joanne P
authors.initials: JP
authors.lastname: Young
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Tucker
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Ahnen
authors.forename: Graeme P
authors.initials: GP
authors.lastname: Young
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
authors.forename: Mark
authors.initials: M
authors.lastname: Clendenning
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: Ingrid
authors.initials: I
authors.lastname: Winship
authors.forename: Finlay A
authors.initials: FA
authors.lastname: Macrae
authors.forename: Jack
authors.initials: J
authors.lastname: Goldblatt
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.forename: Julie
authors.initials: J
authors.lastname: Arnold
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Shanaka R
authors.initials: SR
authors.lastname: Gunawardena
authors.forename: Bharati
authors.initials: B
authors.lastname: Bapat
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia / Q000453:epidemiology; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000209:etiology* / Q000401:mortality; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000453:epidemiology / Q000209:etiology* / Q000401:mortality; D009687:Nuclear Proteins / Q000235:genetics; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D015996:Survival Rate
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