title: Cancer risks for mismatch repair gene mutation carriers: a population-based early onset case-family study.
abstract: OBJECTIVE
  Cancer risks for mismatch repair gene mutation carriers have been derived almost exclusively using families ascertained owing to their strong cancer family history. These may be overestimates, due to analytic problems, and not generalizable. We estimated average cancer risks for mutations identified in population-based early onset colorectal cancer cases (probands) unselected for family history.
  
  
  METHODS
  Data were cancer histories and mutation status (carrier, non-carrier, or unknown) of 17 mismatch repair gene mutation carrier probands with colorectal cancer diagnosed before age 45 (8 hMLH1, 4 hMSH2, 4 hMSH6, 1 hPMS2) and their first- and second-degree relatives. We used modified segregation analysis theory, adjusting for the family being ascertained through the proband being an early onset mutation carrier.
  
  
  RESULTS
  Eleven carrier probands (64%) were from families meeting the Amsterdam II criteria for hereditary nonpolyposis colorectal cancer. The cumulative risk for colorectal cancer (95% confidence interval) to age 70 was 45% (29%-62%) for men and 38% (19%-51%) for women. Corresponding risks were 67% (47%-84%) and 72% (48%-85%) for any hereditary nonpolyposis colorectal cancer-related cancer. Compared with the general population, colorectal cancer incidence for men was approximately 180-fold higher before age 50, but about the same after age 50. For women, incidence was approximately 100-fold higher before age 50 and 7-fold higher thereafter.
  
  
  CONCLUSIONS
  For carriers of the mutations in the mismatch repair genes that cause early onset colorectal cancer, colorectal cancer increases rapidly until age 50, and the incidence decreases to general population levels at older ages.
authors.affiliation: Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Victoria, Australia. m.jenkins@unimelb.edu.au
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: Laura
authors.initials: L
authors.lastname: Baglietto
authors.forename: James G
authors.initials: JG
authors.lastname: Dowty
authors.forename: Christine M
authors.initials: CM
authors.lastname: Van Vliet
authors.forename: Letitia
authors.initials: L
authors.lastname: Smith
authors.forename: Leeanne J
authors.initials: LJ
authors.lastname: Mead
authors.forename: Finlay A
authors.initials: FA
authors.lastname: Macrae
authors.forename: D James B
authors.initials: DJ
authors.lastname: St John
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Jass
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics*; D000251:Adenosine Triphosphatases / Q000235:genetics; D000328:Adult; D000367:Age Factors; D020137:Base Pair Mismatch / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D019683:Penetrance; D018570:Risk Assessment; D012737:Sex Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; 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