Carcinogenesis Advance Access published online on June 9, 2008
Carcinogenesis, doi:10.1093/carcin/bgn136
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Genetic determinants in the metabolism of bladder carcinogens in relation to risk of bladder cancer
1 The Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
2 The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
3 USC/Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California, USA
4 Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA
* To whom correspondence and requests for reprints should be addressed, at Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, 1300 South 2nd Street, Suite 300, Minneapolis, MN 55454, USA; Telephone (612) 625-8065; Fax: (612) 624-0315; Email: jyuan{at}umn.edu.
Genetically determined factors that alter the metabolism of tobacco carcinogens can influence an individual's susceptibility to bladder cancer. The associations between the genotypes of glutathione S-transferase (GST) M1, GSTP1, GSTT1 and N-acetyl-transferase (NAT) 1, and the phenotypes of NAT2 and cytochrome P450 (CYP) 1A2 and bladder cancer risk were examined in a case-control study involving 731 bladder cancer patients and 740 control subjects in Los Angeles County, California. Individual null/low-activity genotypes of GSTM1, GSTT1 and GSTP1 were associated with a 19-48% increase in odds ratio (OR) of bladder cancer. The strongest association was noted for GSTM1 (OR for the null genotype=1.48, 95% confidence interval [CI]=1.19-1.83). When the three GST genes were examined together, there was a monotonic, statistically significant association between increasing number of null/low-activity genotypes and risk (P for trend=0.002). OR (95% CI) for one and 2 or more null/low-activity GST genotypes was 1.42 (1.12-1.81) and 1.71 (1.25-2.34), respectively, relative to the absence of null/low-activity GST genotype. NAT2 slow acetylation was associated with doubled risk of bladder cancer among individuals with known high exposures to carcinogenic arylamines (OR=2.03, 95% CI=1.12-3.69, P=0.02). The effect of NAT2 slow acetylation was even stronger in the presence of 2 or more null/low-activity GST genotypes. There were no associations between bladder cancer risk and NAT1 genotype or CYP1A2 phenotype.
Key Words: aminobiphenyl • cytochrome P450 1A2 • glutathione S-transferase • N-acetyl-transferase • bladder cancer
Received February 25, 2008; revised April 28, 2008; accepted May 30, 2008.
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