Differential expression of hMLH1 and hMSH2 as a potential prognostic biomarker in bladder cancer

G Xinarianos, PhD a, JWF Catto, MBChB a,b, JL Burton, MBChB c FC Hamdy, MD b, M Meuth, PhD a

a) Institute for Cancer Studies, University of Sheffield, United Kingdom, bAcademic Unit of Urology, Royal Hallamshire Hospital, Sheffield, United Kingdom, c Academic Unit of Pathology, University of Sheffield, United Kingdom

AIM: We investigated the frequency of MSI and the expression of two key DNA mismatch repair (MMR) proteins, hMSH2 and hMLH1, in transitional cell carcinomas (TCC) of the bladder. METHODS: One hundred and eleven TCCs, consisting of 74 superficial and 37 invasive tumours, were studied. hMLH1 and hMSH2 expression levels were studied by immunohistochemistry. MSI was examined, on 84 of the tumours, by fluorescent PCR-based assays using the 5 microsatellite markers comprising the Bethesda Consensus Panel. RESULTS: Reduced expression of hMLH1 and hMSH2 was seen in 15% and 16% respectively while reduced expression of either protein was shown in 24% of tumours. Reduced expression of hMLH1 and hMSH2 correlated with advanced stage (p=0.01 and p=0.03 respectively) and grade (p=0.01 and p=0.03 respectively). By five years, reduced expression was associated with fewer recurrences of superficial tumours (p=0.01) and fewer relapses of all tumours (p=0.03). Reduced expression of hMLH1 was associated with smoking status (p=0.003) and daily tobacco consumption (p=0.02). MSI was seen in 6% of the tumours examined. CONCLUSIONS: Differential expression of hMLH1 and hMSH2 appears to be a frequent genetic event in certain TCC cases. MSI is present only in a small subset of cases in our bladder cancer population. Reduced expression of hMLH1 and hMSH2 appears to occur at a late stage in urothelial carcinogenesis and is strongly associated with a better prognostic phenotype but not with MSI. Smoking correlates with reduced expression of hMLH1 suggesting that chemical carcinogens found in tobacco may play a role in DNA MMR deregulation.

KEY WORDS: Bladder Cancer, DNA mismatch repair, microsatellite instability, .

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Familial and Hereditary Cancer.