Susceptibility genes for bladder cancer

S. Horn a, E. Schnakenberga , R. Werdin b, K. Dreikorn b and W. Schloot c

aAdnaGen AG, Hannover-Langenhagen, Lower Saxony Germany bUrological Division, St. Jürgen Hospital of Bremen, Germany cCenter for Human Genetic and Genetic Counselling, University of Bremen, Germany

Aim: The development of cancer in particular bladder cancer may be influenced by genetic factors. The genetic polymorphisms of enzymes like cytochrome P450, N-acetyltransferases and glutathione S-transferases play an important role in the detoxification of numerous exogenous substances. Methods: Using PCR, RFLP and sequencing methods we identified single nucleotide polymorphisms within the phase I gene CYP1A2 and the phase II genes GSTM1 and NAT2. 194 patients suffering from primary bladder cancer and 209 control individuals were analysed. Results: Slow acetylators of NAT2 have been said to be more affected by bladder cancer. We identified slow acetylators to be significantly more prone to primary bladder cancer (odds ratio: 1.88; confidence interval: 1.25-2.82). Heterozygous carriers of the GSTM1 null genotype have a significantly elevated risk of developing bladder cancer (OR: 3.54; 95 % CI, 2.99-4.11). The CYP1A2 gene is characterized by mutation within the promotor region. This mutation is associated with an increased transcription rate leading to an elevated level of highly reactive metabolites. We have identified this mutation significantly more frequent in patients with bladder cancer (OR: 1.54; CI: 1.04-2.28). In addition, for the combination of these NAT2 and CYP1A2 mutations we calculated a significantly potentiated risk for the development of bladder cancer (OR: 4.88; CI: 2.08-11.42). Conclusions: These results indicate that polymorphic genes of phase I and phase II enzymes contribute to an individual susceptibility for the development of cancer f.i. bladder cancer. In addition, the altered detoxification capacity can release also genotoxic effects within tumor suppressor genes.

KEY WORDS: N-acetyltransferase, genetic polymorphisms, slow acetylator.

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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 Predictive Markers.