ABSTRACT: TP53 alterations and patterns of carcinogen exposure in a U.S. population-based study of bladder cancer

The molecular pathology of bladder cancer has been the subject of considerable interest, and current efforts are targeted toward elucidating the interrelationships between individual somatic gene loss and both etiologic and prognostic factors. Mutation of the TP53 gene has been associated with more invasive bladder cancer, and evidence suggests that TP53 mutation, independent of stage, may be predictive of outcome in this disease. However, there is no consensus in the literature that bladder carcinogen exposure is associated with inactivation of the TP53 gene. Work to date has been primarily hospital based and, as such, subject to possible bias associated with selection of more advanced cases for study. We examined exposure relationships with both TP53 gene mutation and TP53 protein alterations in a population-based study of 330 bladder cancer cases in New Hampshire. Tobacco smoking was not associated with TP53 alterations. We found a higher prevalence of TP53 inactivation (i.e., mutation and nuclear accumulation) among hair dye users (odd ratio [OR] 5 4.1; 95% con.dence interval [CI] 1.2–14.7), and the majority of these mutations were transversions. Men who had ‘‘at risk’’ occupations were more likely to have mutated TP53 tumors (OR 5 2.9; 95% CI 1.1–7.6). There also was a relative absence of TP53 mutation (OR 5 0.4; 95% CI 0.0–2.9) and TP53 protein alterations (OR 5 0.6; 95% CI 0.3–1.4) in bladder cancers from individuals with higher arsenic exposure. Our data suggest that there is exposure-speci.c heterogeneity in inactivation of the TP53 pathway in bladder cancers and that integration of the spectrum of pathway alterations in population-based approaches (capturing the full range of exposures to bladder carcinogens) may provide important insights into bladder tumorigenesis.