Epigenetics and Environmental Exposure in Bladder Cancer

Carmen J. Marsit, Ph.D., Hadi Danaee, D.Sc., Karl T. Kelsey, MD, M.O.H, Harvard School of Public Health
Margaret R. Karagas, Ph.D., Dartmouth Medical School
P30ES00002, T32ES07155, and P42ES07373

Background: Epigenetics is defined as the study of changes in gene function that occur without a change in the sequence of nuclear DNA. A common cause of altered gene function is methylation of the gene's promoter region. The promoter is the DNA sequence that is recognized by enzymes involved in the transcription or copying of DNA each time cells divide. Many genes are permanently shut down as a part of normal development, but sometimes that process goes awry, presumably through environmental exposures, and results in the inactivation of genes that otherwise should remain active. Epigenetic changes in gene structure and function have been associated with aging, inherited diseases, and cancer.

Epigenetic alterations are considered critical for the development of bladder cancer. In the United States in 2005 alone, over 60,000 new cases of bladder cancer were diagnosed and over 13,000 people died from the disease. Tobacco smoking, occupational exposure to certain industrial chemicals, and drinking water with high arsenic concentrations are all known risk factors for developing bladder cancer. Studies in laboratory animals suggest that these exposures may act through epigenetic mechanisms. NIEHS-supported researchers at the Harvard School of Public Health and the Dartmouth Medical School have conducted an epidemiologic study of human bladder cancer patients to investigate the relationship of epigenetic silencing of three tumor suppressor genes and exposure to both tobacco and arsenic.

Advance: The three tumor suppressor genes investigated were p16^1NK4A, RASSF1A, and PRSS3. Promoter methlyation of each of these genes occurred in about 30% of bladder cancers. Promoter methylation of RASSF1A, and PRSS3 was associated with advanced tumor stage. Arsenic exposure was associated with RASSF1A, and PRSS3 promoter methylation but not p16^1NK4A methylation. Cigarette smoking was associated with greater than a two-fold increased risk of promoter methylation for p16^1NK4A only with greater risk seen in people who were still smoking at the time of diagnosis.

Implications: The results indicate that in bladder cancer there are specific associations between exposure to arsenic and tobacco smoke and methylation of the promoter region of tumor suppressor genes. This study adds human data to the body of knowledge from laboratory animal studies which have shown that bladder cancer may result from epigenetic alterations instead of mutations or genetic toxicology. It also suggests that exposure to carcinogens in tobacco smoke may silence specific genes in the time period close to the clinical manifestation of tumors, which may have important clinical implications for patients.

Citation: Marsit CJ, Karagas MR, Danaee H, Liu M, Andrew A, Schned A, Nelson HH, Kelsey KT. Carcinogen exposure and gene promoter hypermethylation in bladder cancer. Carcinogenesis. 2006 Jan;27(1):112-6.