title: Frequent mismatch-repair defects link prostate cancer to Lynch syndrome.
abstract: BACKGROUND
  A possible role for prostate cancer in Lynch syndrome has been debated based on observations of mismatch-repair defective tumors and reports of an increased risk of prostate cancer in mutation carriers. Potential inclusion of prostate cancer in the Lynch syndrome tumor spectrum is relevant for family classification, risk estimates and surveillance recommendations in mutation carriers.
  
  
  METHODS
  We used the population-based Danish HNPCC-register to identify all prostate cancers that developed in mutation carriers and in their first-degree relatives from 288 Lynch syndrome families. The tumors were evaluated for clinicopathologic features and mismatch-repair status, and the cumulative risk of prostate cancer was determined.
  
  
  RESULTS
  In total, 28 prostate cancers developed in 16 mutation carriers and in 12 first-degree relatives at a median age of 63 years. The majority of the tumors were high-grade tumors with Gleason scores 8-10. Prostate cancer was associated with mutations in MSH2, MLH1 and MSH6 with loss of the respective mismatch repair protein in 69 % of the tumors, though a MSI-high phenotype was restricted to 13 % of the tumors. The cumulative risk of prostate cancer at age 70 was 3.7 % (95 % CI: 2.3-4.9).
  
  
  CONCLUSIONS
  We provide evidence to link prostate cancer to Lynch syndrome through demonstration of MMR defective tumors and an increased risk of the disease, which suggests that prostate cancer should be considered in the diagnostic work-up of Lynch syndrome.
authors.affiliation: Institute of Clinical Sciences, Division of Oncology and Pathology, Lund University, SE-22381, Lund, Sweden.
authors.forename: Mev
authors.initials: M
authors.lastname: Dominguez-Valentin
authors.affiliation: Institute of Clinical Sciences, Division of Oncology and Pathology, Lund University, SE-22381, Lund, Sweden.
authors.forename: Patrick
authors.initials: P
authors.lastname: Joost
authors.affiliation: HNPCC-Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.
authors.forename: Christina
authors.initials: C
authors.lastname: Therkildsen
authors.affiliation: Institute of Clinical Sciences, Division of Oncology and Pathology, Lund University, SE-22381, Lund, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Jonsson
authors.affiliation: Institute of Clinical Sciences, Division of Oncology and Pathology, Lund University, SE-22381, Lund, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Rambech
authors.affiliation: Institute of Clinical Sciences, Division of Oncology and Pathology, Lund University, SE-22381, Lund, Sweden. mef.nilbert@med.lu.se.|HNPCC-Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark. mef.nilbert@med.lu.se.
authors.forename: Mef
authors.initials: M
authors.lastname: Nilbert
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000230:Adenocarcinoma / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D003718:Denmark; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics*; D012042:Registries
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein
keywords: MLH1; MSH2; MSH6; Microsatellite instability; Mismatch repair deficiency