Abstract
AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore C61 Objectives: Superficial bladder cancers (SBC) have a 60-70% recurrence rate after transurethral resection, and 10-20% of recurrences progress to invasive cancer. Post-transurethral resection intravesical Bacillus Calmette-Guerin (BCG) instillation has been the ‘gold-standard’ treatment for high risk SBC, for which 20-40% of patients do not respond. There are also frequent, potentially serious side effects to BCG therapy. Although clinical and pathologic variables to predict BCG response and cancer recurrence have been extensively studied, little is known of the role of underlying host genetic susceptibility factors, such as genetic polymorphisms. The NRAMP1 gene has been implicated in susceptibility to tuberculosis and to BCG response in murine models. The Human glutathione peroxidase 1 (hGPX1) is a selenium-dependent enzyme that participates in detoxification of hydrogen peroxide, organic peroxides, and possibly cigarette smoke-derived oxidative radicals. An association between hGPX1 and NRAMP1, and bladder cancer recurrence has been suggested. We aim to determine the predictive value of NRAMP1 and hGPX1 gene polymorphisms in superficial bladder cancer recurrence and response to BCG therapy. Methods: Peripheral blood DNA was prospectively obtained from 99 high risk superficial bladder cancer patients, who underwent post-resection intravesical regimes of BCG (81mg, n=50 or 27mg, n=19) or BCG (27mg) with interferon alpha (IFNa) (n=30), and followed-up for a mean of 4.5 years. The (GT)n and D534N polymorphisms in the NRAMP1 gene, and the Pro198Leu polymorphism in the hGPX1 gene were tested with restriction fragment length polymorphisms and DNA sequencing following PCR amplification. Data was analyzed using Chi-square analysis, multiple logistic regression and Kaplan-Meier curves. Results: The D534N G:A genotype was found to be protective towards cancer recurrence (p=0.016) and cancer-specific death (p=0.036). The presence of allele 3 in the (GT)n gene polymorphism was found to correlate with higher recurrence in BCG treated patients (p=0.003), and had shorter recurrence-free survival (p=0.024) and progression-free survival (p=0.005) in patients treated with a combination of BCG and IFNa. The hGPX1 CC genotype was shown to be protective (p=0.014), while the variant CT genotype (Pro/Leu) was associated with increased bladder cancer recurrence and decreased time to recurrence (p=0.03) after BCG therapy. Conclusion: Our findings suggest that polymorpisms in the NRAMP1 and hGPX1 genes correlate with response to BCG therapy in bladder cancer patients. They may serve as molecular markers to predict BCG failure and cancer recurrence.
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