Carcinogen exposure and gene promoter hypermethylation in bladder cancer.
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, p16(INK4A), RASSF1A and PRSS3, and exposure to both tobacco and arsenic in bladder cancer. Promoter methylation of each of these genes occurred in approximately 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.
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Carmen J
CJ
Marsit
Margaret R
MR
Karagas
Hadi
H
Danaee
Mei
M
Liu
Angeline
A
Andrew
Alan
A
Schned
Heather H
HH
Nelson
Karl T
KT
Kelsey
D000328:Adult; D000368:Aged; D001151:Arsenic / Q000009:adverse effects*; D002295:Carcinoma, Transitional Cell / Q000453:epidemiology / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D020868:Gene Silencing; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009513:New Hampshire / Q000453:epidemiology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012907:Smoking / Q000235:genetics*; D014357:Trypsin / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000453:epidemiology / Q000235:genetics*
D019941:Cyclin-Dependent Kinase Inhibitor p16; C411762:RASSF1 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C040749:PRSS3 protein, human; D014357:Trypsin; D001151:Arsenic