title: Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance.
abstract: OBJECTIVE
  Hereditary nonpolyposis colorectal carcinoma (HNPCC) is caused by a mutated mismatch repair (MMR) gene. The aim of our study was to determine the cumulative risk of developing cancer in a large series of MSH6 mutation carriers.
  
  
  METHODS
  Mutation analysis was performed in 20 families with a germline mutation in MSH6. We compared the cancer risks between MSH6 and MLH1/MSH2 mutation carriers. Microsatellite instability (MSI) analysis and immunohistochemistry (IHC) were performed in the available tumors.
  
  
  RESULTS
  A total of 146 MSH6 mutation carriers were identified. In these carriers, the cumulative risk for colorectal carcinoma was 69% for men, 30% for women, and 71% for endometrial carcinoma at 70 years of age. The risk for all HNPCC-related tumors was significantly lower in MSH6 than in MLH1 or MSH2 mutation carriers (P = 0.002). In female MSH6 mutation carriers, the risk for colorectal cancer was significantly lower (P = 0.0049) and the risk for endometrial cancer significantly higher (P = 0.02) than in MLH1 and MSH2 mutation carriers. In male carriers, the risk for colorectal cancer was lower in MSH6 mutation carriers, but the difference was not significant (P = 0.0854). MSI analysis in colorectal tumors had a sensitivity of 86% in predicting a MMR defect. IHC in all tumors had a sensitivity of 90% in predicting a mutation in MSH6.
  
  
  CONCLUSIONS
  We recommend starting colonoscopic surveillance in female MSH6 mutation carriers from age 30 years. Prophylactic hysterectomy might be considered in carriers older than 50 years. MSI and IHC analysis are sensitive tools to identify families eligible for MSH6 mutation analysis.
authors.affiliation: Center of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. y.m.c.hendriks@lumc.nl
authors.forename: Yvonne M C
authors.initials: YM
authors.lastname: Hendriks
authors.forename: Anja
authors.initials: A
authors.lastname: Wagner
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.forename: Fred
authors.initials: F
authors.lastname: Menko
authors.forename: Astrid
authors.initials: A
authors.lastname: Stormorken
authors.forename: Franz
authors.initials: F
authors.lastname: Quehenberger
authors.forename: Lodewijk
authors.initials: L
authors.lastname: Sandkuijl
authors.forename: Pal
authors.initials: P
authors.lastname: Møller
authors.forename: Maurizio
authors.initials: M
authors.lastname: Genuardi
authors.forename: Hans
authors.initials: H
authors.lastname: Van Houwelingen
authors.forename: Carli
authors.initials: C
authors.lastname: Tops
authors.forename: Marjo
authors.initials: M
authors.lastname: Van Puijenbroek
authors.forename: Paul
authors.initials: P
authors.lastname: Verkuijlen
authors.forename: Gemma
authors.initials: G
authors.lastname: Kenter
authors.forename: Anneke
authors.initials: A
authors.lastname: Van Mil
authors.forename: Hanne
authors.initials: H
authors.lastname: Meijers-Heijboer
authors.forename: Gita B
authors.initials: GB
authors.lastname: Tan
authors.forename: Martijn H
authors.initials: MH
authors.lastname: Breuning
authors.forename: Riccardo
authors.initials: R
authors.lastname: Fodde
authors.forename: Juul Th
authors.initials: JT
authors.lastname: Wijnen
authors.forename: Annette H J T
authors.initials: AH
authors.lastname: Bröcker-Vriends
authors.forename: Hans
authors.initials: H
authors.lastname: Vasen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D002352:Carrier Proteins; D043171:Chromosomal Instability / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000150:complications / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005190:Family; D005260:Female; D033142:Genetic Services; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics; D009369:Neoplasms / Q000209:etiology / Q000235:genetics; D009687:Nuclear Proteins; D012306:Risk
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1