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a Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA b Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA c Department of Pathology, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA
Key Words: bladder cancer • DNA methylation • epigenetic • arsenic • tobacco smoke
Address for correspondence: Carmen J. Marsit, Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Building I, Room 611, Boston, MA 02115. Voice: 617-432-4677; fax: 617-432-0107. e-mail: cmarsit{at}hsph.harvard.edu
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. Animal and in vitro studies have suggested that arsenic, tobacco carcinogens, and other exposures may act through epigenetic mechanisms. We, therefore, examined, in a population-based study of human bladder cancer (n = 351), the relationship between epigenetic silencing of the tumor-suppressor genes, p16INK4A, RASSF1A, PRSS3, and the four SFRP genes and exposure to both tobacco and arsenic in bladder cancer. Promotor methylation silencing of each of these genes occurred in approximately 30–50% of bladder cancers. Epigenetic silencing of RASSF1A and PRSS3 and any of the SFRP genes were each significantly associated with advanced tumor stage (P < 0.001, P < 0.04, and P < 0.005, respectively). Arsenic exposure, measured as toenail arsenic, was associated with RASSF1A (P < 0.02) and PRSS3 (P < 0.1) but not p16INK4A or SFRP promotor methylation, in models adjusted for stage and other risk factors. Cigarette smoking was associated with a greater than twofold increased risk of promotor methylation of the p16INK4A gene, with greater risk seen in patients with exposures more recent to disease diagnosis, and smoking was also significantly associated with any SFRP gene methylation (P < 0.01). These results from human bladder tumors, add to the body of animal and in vitro evidence that suggests bladder carcinogens play a crucial role in the induction of important epigenetic alterations.
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