title: Urinary Tract Cancer in Lynch Syndrome; Increased Risk in Carriers of MSH2 Mutations.
abstract: OBJECTIVE
  To evaluate the risk of urothelial cancer in the upper urinary tract and the bladder, determine the contribution from the different mismatch-repair genes, and define clinical characteristics of urothelial cancer in Lynch syndrome.
  
  
  METHODS
  The national hereditary nonpolyposis colorectal cancer registry was used to identify all 288 Lynch syndrome families in Denmark. Urothelial cancers that developed in mutation carriers and in their first-degree relatives were identified, mismatch-repair status was assessed, clinicopathologic variables were defined, and cumulative lifetime risks were determined.
  
  
  RESULTS
  In total, 48 cancers of the ureter, 34 cancers of the renal pelvis, and 54 urinary bladder cancers developed at a mean age of 61 (24-89) years. The tumors were typically of high grade, showed loss of mismatch-repair protein expression in 90% of the tumors and microsatellite instability in 23% of the tumors. Mutations in MSH2 were overrepresented (73%), and MSH2 mutation carriers were at a significantly increased risk of developing urinary tract cancer compared with individuals with mutations in MLH1 or MSH6.
  
  
  CONCLUSIONS
  Cancers of the upper urinary tract and the urinary bladder are included in the Lynch syndrome tumor spectrum. Urothelial cancers are predominantly linked to MSH2 mutations, which suggest that surveillance should be targeted at individuals with mutations herein.
authors.affiliation: Department of Oncology and Pathology, Institute of Clinical Sciences, Lund University, Lund, Sweden. Electronic address: patrick.joost@med.lu.se.
authors.forename: Patrick
authors.initials: P
authors.lastname: Joost
authors.affiliation: Department of Oncology and Pathology, Institute of Clinical Sciences, Lund University, Lund, Sweden; HNPCC-Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.
authors.forename: Christina
authors.initials: C
authors.lastname: Therkildsen
authors.affiliation: Department of Oncology and Pathology, Institute of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Mev
authors.initials: M
authors.lastname: Dominguez-Valentin
authors.affiliation: Department of Oncology and Pathology, Institute of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Jönsson
authors.affiliation: Department of Oncology and Pathology, Institute of Clinical Sciences, Lund University, Lund, Sweden; HNPCC-Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.
authors.forename: Mef
authors.initials: M
authors.lastname: Nilbert
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000032:analysis / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D029681:Arabidopsis Proteins / Q000032:analysis / Q000235:genetics; D002295:Carcinoma, Transitional Cell / Q000453:epidemiology / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000032:analysis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics; D003718:Denmark / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000032:analysis / Q000235:genetics*; D009378:Neoplasms, Multiple Primary / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D016609:Neoplasms, Second Primary / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics; D010375:Pedigree; D012307:Risk Factors; D014571:Urologic Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases; D029681:Arabidopsis Proteins; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009687:Nuclear Proteins; C501486:MLH1 protein, human; C121985:AT4G02070 protein, Arabidopsis; C094934:PMS2 protein, human; C497172:MSH2 protein, human