title: Risks of Lynch syndrome cancers for MSH6 mutation carriers.
abstract: BACKGROUND
  Germline mutations in MSH6 account for 10%-20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their cancer risks are uncertain.
  
  
  METHODS
  We identified 113 families of MSH6 mutation carriers from five countries that we ascertained through family cancer clinics and population-based cancer registries. Mutation status, sex, age, and histories of cancer, polypectomy, and hysterectomy were sought from 3104 of their relatives. Age-specific cumulative risks for carriers and hazard ratios (HRs) for cancer risks of carriers, compared with those of the general population of the same country, were estimated by use of a modified segregation analysis with appropriate conditioning depending on ascertainment.
  
  
  RESULTS
  For MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as follows: for colorectal cancer, 22% (95% confidence interval [CI] = 14% to 32%) and 44% (95% CI = 28% to 62%) for men and 10% (95% CI = 5% to 17%) and 20% (95% CI = 11% to 35%) for women; for endometrial cancer, 26% (95% CI = 18% to 36%) and 44% (95% CI = 30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI = 16% to 37%) and 47% (95% CI = 32% to 66%) for men and 40% (95% CI = 32% to 52%) and 65% (95% CI = 53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR = 7.6, 95% CI = 5.4 to 10.8), which was independent of sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial cancer (HR = 25.5, 95% CI = 16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR = 6.0, 95% CI = 3.4 to 10.7).
  
  
  CONCLUSIONS
  We have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers.
authors.affiliation: Cancer Epidemiology Centre, Victorian Cancer Registry, Carlton, Victoria, Australia.
authors.forename: Laura
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authors.lastname: Baglietto
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.forename: James G
authors.initials: JG
authors.lastname: Dowty
authors.forename: Darren M
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authors.forename: Annette H J T
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authors.lastname: Cartwright
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authors.forename: Heather
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authors.forename: Daniel
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authors.forename: Sven
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authors.forename: Joanne
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authors.forename: Michael D
authors.initials: MD
authors.lastname: Walsh
authors.forename: Jeremy
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authors.lastname: Jass
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authors.lastname: Macrae
authors.forename: Yoland
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authors.lastname: Antill
authors.forename: Ingrid M
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authors.lastname: Winship
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: Jack
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authors.lastname: Goldblatt
authors.forename: Susan
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authors.lastname: Parry
authors.forename: Graeme
authors.initials: G
authors.lastname: Suthers
authors.forename: Barbara
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authors.lastname: Leggett
authors.forename: Malinda
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authors.lastname: Butz
authors.forename: Melyssa
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authors.lastname: Aronson
authors.forename: Jenny N
authors.initials: JN
authors.lastname: Poynter
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.forename: Loic
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authors.lastname: Le Marchand
authors.forename: Robert
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authors.lastname: Haile
authors.forename: Steve
authors.initials: S
authors.lastname: Gallinger
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: John
authors.initials: J
authors.lastname: Potter
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
authors.forename: Hans F
authors.initials: HF
authors.lastname: Vasen
authors.forename: Malcolm G
authors.initials: MG
authors.lastname: Dunlop
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Mark A
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authors.lastname: Jenkins
mesh_terms: D000328:Adult; D017677:Age Distribution; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia / Q000453:epidemiology; D002170:Canada / Q000453:epidemiology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology* / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000453:epidemiology / Q000235:genetics; D005060:Europe / Q000453:epidemiology; D005260:Female; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics; D009520:New Zealand / Q000453:epidemiology; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D017678:Sex Distribution; D012737:Sex Factors; D014481:United States / Q000453:epidemiology
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein