title: p53 mutations in bladder cancer: evidence for exogenous versus endogenous risk factors.
abstract: 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.
authors: Epidemiology Branch, National Institute of Environmental Health Sciences/NIH, 111 Alexander Drive, Research Triangle Park, North Carolina 27709, USA.
authors: Jane C
authors: JC
authors: Schroeder
authors: Kathleen
authors: K
authors: Conway
authors: Yu
authors: Y
authors: Li
authors: Kusum
authors: K
authors: Mistry
authors: Douglas A
authors: DA
authors: Bell
authors: Jack A
authors: JA
authors: Taylor
mesh_terms: D000123:Acetyltransferases / Q000235:genetics; D000368:Aged; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D002295:Carcinoma, Transitional Cell / Q000201:enzymology / Q000209:etiology* / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007527:Isoenzymes; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016273:Occupational Exposure; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012737:Sex Factors; D012907:Smoking / Q000009:adverse effects; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000209:etiology* / Q000235:genetics*
chemical_list: D000123:Acetyltransferases; D001191:Arylamine N-Acetyltransferase; D005982:Glutathione Transferase; D007527:Isoenzymes; C089384:N-acetyltransferase 1; C478900:NAT2 protein, human