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p53 Mutations in Bladder Cancer

Evidence for Exogenous versus Endogenous Risk Factors

Epidemiology Branch [J. C. S., J. A. T.], Laboratory of Computational Biology and Risk Analysis [D. A. B.], and Laboratory of Molecular Carcinogenesis [J. A. T.], National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, and Department of Epidemiology, University of North Carolina School of Public Health [K. C., Y. L.] and University of North Carolina Lineberger Comprehensive Cancer Center [K. C., Y. L., K. M.], University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599

Bladder cancer is associated with smoking, occupational exposures, and glutathione S-transferase (GST) M1 and N-acetyltransferase (NAT) 2 polymorphisms that may influence carcinogen metabolism, but somatic p53mutations are often CpG dinucleotide G:C-A:T transitions that can occur spontaneously. We conducted a case-control study to determine whether p53mutation characteristics might distinguish cases with environmental versus endogenous causes. p53exons 4–9 were amplified from 146 bladder tumors by PCR, screened by single-strand conformational polymorphism analysis, and sequenced. Thirty-one cases were p53-positive, and 112 were p53-negative (germ line or silent). G:C-A:T transitions were also subclassified as CpG or non-CpG. Cases and 215 clinic controls were interviewed. GSTM1, NAT1, and NAT2 polymorphisms were assayed from peripheral blood. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic and polytomous regression. Case-control ORs for smoking, occupations, and NAT1*10genotype were similar for p53-positive and p53-negative cases. Associations with GSTM1-null and NAT2-slow genotypes were somewhat stronger for p53-positive [OR, 3.3; CI, 1.4–7.8 (GSTM1 null); OR, 1.8; CI, 0.8–4.0 (NAT2 slow)] than p53-negative cases [OR, 1.5; CI:0.9–2.3 (GSTM1 null); OR, 0.9; CI, 0.6–1.4 (NAT2 slow)]. Smoking was strongly associated with CpG G:C-A:T (OR, 15.3; CI:3.6–65) versus other G:C-A:T (OR, 1.8; CI, 0.3–9.8). NAT2 slow genotypes were also associated with CpG G:C-A:T (OR, 6.2; CI:0.7–52), whereas GSTM1 null was associated with non-CpG G:C-A:T (OR, 7.8; CI, 0.9–65). Associations were not substantially different for case subtypes defined by p53mutation status alone. Estimates for p53 subtypes were imprecise but support in vitro evidence that some CpG G:C-A:T transitions may be caused by smoking and other environmental mutagens.

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