Genetic analysis of hMLH1 in transitional cell carcinoma of the urinary tract: Promoter methylation or mutation

Purpose: Loss of DNA mismatch repair due to diminished expression or mutati on of hMLH1 is associated with genomic instability followed by cancer. We p erformed genetic analyses of hMLH1 to determine whether hMLH1 alterations h ave a role in urothelial tumorigenesis. Materials and Methods: We examined genomic DNA from 118 sporadic transition al cell carcinomas, including 83 bladder and 35 renal pelvis or ureter case s, for aberrant promoter methylation and mutation in the hMLH1 gene. Immuno histochemical reactivity to hMLH1 protein and genome instability in these t ransitional cell carcinomas were also studied. Results: Two of the 118 cases (1.7%) had microsatellite instability and hML H1 promoter methylation with loss of or reduced hMLH1 protein expression, A single transitional cell carcinoma (0.8%) without microsatellite instabili ty had an hMLH1 missense mutation with a C-to-T transition, resulting in th e substitution Arg217 --> Cys. Immunostaining with anti-hMLH1 antibody was found in this transitional cell carcinoma. Conclusions: To our knowledge these findings provide the first in vivo evid ence for the type and frequency of possible involvement of promoter methyla tion and mutation of hMLH1 in sporadic urothelial transitional cell carcino ma. They also suggest that hMLH1 alterations may not account for many cases of sporadic transitional cell carcinoma tumorigenesis.