Human Mismatch Repair Protein Expression in Bladder Cancer
Francesca Khani, Evanguelos Xylinas, Bjoern Volkmer, Luis Kluth, Douglas S Scherr, Mark A Rubin, Juan Miguel Mosquera, Richard E Hautmann, Rainer Kuefer, Shahrokh F Shariat, Brian D Robinson. Weill Cornell Medical College, New York, NY; University of Ulm, Ulm, Germany
Background: In urothelial carcinoma of the bladder (UCB), decreased expression of mismatch repair proteins MSH2 and, to a lesser extent, MLH1 have been found to be associated with higher grade, higher stage, and worse prognosis. This association was independent of molecular results of microsatellite instability testing. Evaluation of these markers in a large consecutive series of radical cystectomy (RC) patients has not been reported. Furthermore, no studies have investigated mismatch repair proteins MSH6 or MGMT expression. We evaluated MLH1, MSH6, and MGMT in a series of 383 consecutive RCs and examined their association with pathologic features and clinical outcomes.
Design: We utilized tissue microarrays (TMAs) containing samples from 383 consecutive UCB patients treated with RC between 1988 and 2003 at one academic center. The median follow-up in our cohort was 129 months (IQR 111). The TMAs were stained using monoclonal antibodies against MLH1, MSH6, and MGMT. Expression (absent vs. expressed) was evaluated by two pathologists who were blinded to clinical outcome.
Results: Loss of MLH1 and MSH6 expression was observed 1.8% (6/337) and 17.9% (60/336) of UCBs, respectively. MGMT was aberrantly expressed in 24.8% (240/319) of UCBs. Loss of MLH-1 was significantly associated with decreased cancer-specific survival (p=0.033) but was not associated with pathologic stage, grade, overall survival, or disease free survival. Loss of MSH6 and aberrant expression of MGMT were not significantly associated with pathologic stage or grade, nor were they associated with overall, disease-free, or cancer-specific survival.
Conclusions: The results of our study suggest that loss of MLH1 expression might be involved in tumor pathogenesis and progression of some UCBs. Although we did not find loss of MLH1 to be associated with pathologic stage or grade, its association with decreased cancer-specific survival suggests that MLH1 may be a potentially useful prognostic biomarker for UCB. MSH6 and MGMT expression, in our cohort, were not significant predictors of UCB behavior. Evaluation of mismatch repair proteins MSH2 and PMS2 is ongoing.
Category: Genitourinary (including renal tumors)
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 200, Tuesday Afternoon