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, Karl T. Kelsey

Research output: Contribution to journalArticlepeer-review

158 Scopus citations

Abstract

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 dence that suggests a role in epigenetic alterations for bladder carcinogens.

Original languageEnglish (US)
Pages (from-to)112-116
Number of pages5
JournalCarcinogenesis
Volume27
Issue number1
DOIs
StatePublished - Jan 2006

Bibliographical note

Funding Information:
This work was supported by NIEHS Superfund Center Grant 00002, NCI grant R01 CA100679, and NIEHS toxicology and environmental health sciences training grant T32 ES007155 to C.J.M. and H.D.

Fingerprint Dive into the research topics of 'Carcinogen exposure and gene promoter hypermethylation in bladder cancer'. Together they form a unique fingerprint.

Cite this