Journal Article

Carcinogen exposure and gene promoter hypermethylation in bladder cancer

Carmen J. Marsit, Margaret R. Karagas, Hadi Danaee, Mei Liu, Angeline Andrew, Alan Schned, Heather H. Nelson and Karl T. Kelsey

in Carcinogenesis

Volume 27, issue 1, pages 112-116
Published in print January 2005 | ISSN: 0143-3334
Published online June 2005 | e-ISSN: 1460-2180 | DOI:
Carcinogen exposure and gene promoter hypermethylation in bladder cancer

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Tobacco smoking, certain occupational exposures, and exposure to inorganic arsenic in drinking water have been associated with the occurrence of bladder cancer. However, in these tumors the exposure-associated pattern of somatic alterations in genes in the causal pathway for disease has been poorly characterized. In particular, the mechanism by which arsenic induces bladder cancer and the effects of lower environmental levels of exposure remain uncertain. Animal and in-vitro studies have suggested that arsenic and other exposures may act through epigenetic mechanisms. We, therefore, examined, in a population-based study of human bladder cancer, the relationship between epigenetic silencing of three tumor suppressor genes, p16INK4A, RASSF1A and PRSS3, and exposure to both tobacco and arsenic in bladder cancer. Promoter methylation of each of these genes occurred in ∼30% of bladder cancers, and both RASSF1A and PRSS3 promoter methylation were associated with advanced tumor stage (P < 0.001 and P < 0.04, respectively). Arsenic exposure, measured as toenail arsenic, was associated with RASSF1A (P < 0.02) and PRSS3 (P < 0.1) but not p16INK4A promoter methylation, in models adjusted for stage and other factors. Cigarette smoking was associated with a >2-fold increased risk of promoter methylation of the p16INK4A gene only, with greater risk seen in patients with exposures more recent to disease diagnosis. These results, from human bladder tumors, add to the body of animal and in vitro evidence that suggests a role in epigenetic alterations for bladder carcinogens.

Keywords: CI, confidence interval; SAM, S-adenosyl methionine; TCC, transitional cell carcinoma; OR, odds ratio

Journal Article.  4088 words. 

Subjects: Clinical Cytogenetics and Molecular Genetics

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