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Carcinogen Exposure and Epigenetic Silencing in Bladder Cancer
Author(s) -
MARSIT CARMEN J.,
KARAGAS MARGARET R.,
SCHNED ALAN,
KELSEY KARL T.
Publication year - 2006
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1371.031
Subject(s) - epigenetics , bladder cancer , methylation , gene silencing , dna methylation , cancer research , cancer , carcinogen , biology , medicine , gene , genetics , gene expression
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, p16 INK4A , 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 p16 INK4A 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 p16 INK4A 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.