Purpose: 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.
Materials and 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.