title: Genetic analysis of hMLH1 in transitional cell carcinoma of the urinary tract: promoter methylation or mutation.
abstract: OBJECTIVE
  Loss of DNA mismatch repair due to diminished expression or mutation of hMLH1 is associated with genomic instability followed by cancer. We performed genetic analyses of hMLH1 to determine whether hMLH1 alterations have a role in urothelial tumorigenesis.
  
  
  METHODS
  We examined genomic DNA from 118 sporadic transitional cell carcinomas, including 83 bladder and 35 renal pelvis or ureter cases, for aberrant promoter methylation and mutation in the hMLH1 gene. Immunohistochemical reactivity to hMLH1 protein and genome instability in these transitional cell carcinomas were also studied.
  
  
  RESULTS
  Two of the 118 cases (1.7%) had microsatellite instability and hMLH1 promoter methylation with loss of or reduced hMLH1 protein expression. A single transitional cell carcinoma (0.8%) without microsatellite instability had an hMLH1 missense mutation with a C-to-T transition, resulting in the substitution Arg217 --> Cys. Immunostaining with antihMLH1 antibody was found in this transitional cell carcinoma.
  
  
  CONCLUSIONS
  To our knowledge these findings provide the first in vivo evidence for the type and frequency of possible involvement of promoter methylation and mutation of hMLH1 in sporadic urothelial transitional cell carcinoma. They also suggest that hMLH1 alterations may not account for many cases of sporadic transitional cell carcinoma tumorigenesis.
authors.affiliation: Department of Pathology II and Urology, Kochi Medical School, Nankoku, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Furihata
authors.forename: T
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Y
authors.initials: Y
authors.lastname: Ohtsuki
authors.forename: N
authors.initials: N
authors.lastname: Terao
authors.forename: M
authors.initials: M
authors.lastname: Kuwahara
authors.forename: T
authors.initials: T
authors.lastname: Shuin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020137:Base Pair Mismatch; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins; D019175:DNA Methylation; D004260:DNA Repair; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009154:Mutation; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics*; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014571:Urologic Neoplasms / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1