title: Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome.
abstract: BACKGROUND
  Lynch syndrome is a highly penetrant cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes. We estimated the risks of primary cancers other than colorectal cancer following a diagnosis of colorectal cancer in mutation carriers.
  
  
  METHODS
  We obtained data from the Colon Cancer Family Registry for 764 carriers of an MMR gene mutation (316 MLH1, 357 MSH2, 49 MSH6, and 42 PMS2), who had a previous diagnosis of colorectal cancer. The Kaplan-Meier method was used to estimate their cumulative risk of cancers 10 and 20 years after colorectal cancer. We estimated the age-, sex-, country- and calendar period-specific standardized incidence ratios (SIRs) of cancers following colorectal cancer, compared with the general population.
  
  
  RESULTS
  Following colorectal cancer, carriers of MMR gene mutations had the following 10-year risk of cancers in other organs: kidney, renal pelvis, ureter, and bladder (2%, 95% confidence interval [CI] = 1% to 3%); small intestine, stomach, and hepatobiliary tract (1%, 95% CI = 0.2% to 2%); prostate (3%, 95% CI = 1% to 5%); endometrium (12%, 95% CI = 8% to 17%); breast (2%, 95% CI = 1% to 4%); and ovary (1%, 95% CI = 0% to 2%). They were at elevated risk compared with the general population: cancers of the kidney, renal pelvis, and ureter (SIR = 12.54, 95% CI = 7.97 to 17.94), urinary bladder (SIR = 7.22, 95% CI = 4.08 to 10.99), small intestine (SIR = 72.68, 95% CI = 39.95 to 111.29), stomach (SIR = 5.65, 95% CI = 2.32 to 9.69), and hepatobiliary tract (SIR = 5.94, 95% CI = 1.81 to 10.94) for both sexes; cancer of the prostate (SIR = 2.05, 95% CI = 1.23 to 3.01), endometrium (SIR = 40.23, 95% CI = 27.91 to 56.06), breast (SIR = 1.76, 95% CI = 1.07 to 2.59), and ovary (SIR = 4.19, 95% CI = 1.28 to 7.97).
  
  
  CONCLUSIONS
  Carriers of MMR gene mutations who have already had a colorectal cancer are at increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers.
authors.affiliation: Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, Melbourne School of Population Health, Level 3, 207 Bouverie Street, The University of Melbourne, VIC 3010, Australia.
authors.forename: Aung Ko
authors.initials: AK
authors.lastname: Win
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.forename: Joanne P
authors.initials: JP
authors.lastname: Young
authors.forename: Finlay A
authors.initials: FA
authors.lastname: Macrae
authors.forename: Graeme P
authors.initials: GP
authors.lastname: Young
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Williamson
authors.forename: Susan
authors.initials: S
authors.lastname: Parry
authors.forename: Jack
authors.initials: J
authors.lastname: Goldblatt
authors.forename: Lara
authors.initials: L
authors.lastname: Lipton
authors.forename: Ingrid
authors.initials: I
authors.lastname: Winship
authors.forename: Barbara
authors.initials: B
authors.lastname: Leggett
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Tucker
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
authors.forename: Mark
authors.initials: M
authors.lastname: Clendenning
authors.forename: Christophe
authors.initials: C
authors.lastname: Rosty
authors.forename: Julie
authors.initials: J
authors.lastname: Arnold
authors.forename: A Joan
authors.initials: AJ
authors.lastname: Levine
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
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: 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; D000368:Aged; D001315:Australia / Q000453:epidemiology; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000235:genetics; D002170:Canada / Q000453:epidemiology; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000150:complications* / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000150:complications* / Q000235:genetics; D015986:Confounding Factors, Epidemiologic; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004067:Digestive System Neoplasms / Q000453:epidemiology* / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D053208:Kaplan-Meier Estimate; 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; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D014481:United States / Q000453:epidemiology; D014565:Urogenital Neoplasms / Q000453:epidemiology* / Q000235:genetics
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