Carcinogenesis Advance Access originally published online on January 23, 2004
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Carcinogenesis, Vol. 25, No. 6, 1063-1067,
June 2004
Carcinogenesis vol.25 no.6 © Oxford University Press 2004; all rights reserved.
ARTICLE |
Plutonium targets the p16 gene for inactivation by promoter hypermethylation in human lung adenocarcinoma
1 Lovelace Respiratory Research Institute, Lung Cancer Program, 2425 Ridgecrest Drive SE, Albuquerque, NM 87108, USA, 2 Keck School of Medicine, University of Southern California, Los Angeles, CA 91105, USA and 3 Southern Ural Biophysics Institute, Ozyorsk, Russia
4 To whom correspondence should be addressed Email: sbelinsk{at}lrri.org
Lung cancer from radon or 239plutonium exposure has been linked to 
-particles that damage DNA through large deletions and point mutations. We investigated the involvement of an epigenetic mechanism, gene inactivation by promoter hypermethylation in adenocarcinomas from plutonium-exposed workers at MAYAK, the first Russian nuclear enterprise established to manufacture weapons plutonium. Adenocarcinomas were collected retrospectively from 71 workers and 69 non-worker controls. Lung adenocarcinomas were examined from workers and non-worker controls for methylation of the CDKN2A (p16), O6-methylguanine-DNA methyltransferase (MGMT), death associated protein kinase (DAP-K), and Ras effector homolog 1 genes (RASSF1A). The prevalence for methylation of the MGMT or DAP-K genes did not differ between workers and controls, while a higher prevalence for methylation of the RASSF1A gene was seen in tumors from controls. In marked contrast, the prevalence for methylation of p16, a key regulator of the cell cycle, was increased significantly (P = 0.03) in tumors from workers compared with non-worker controls. Stratification of plutonium exposure into tertiles also revealed a striking dose response for methylation of the p16 gene (P = 0.008). Workers in the plutonium plant where exposure to internal radiation was highest had a 3.5 times (C.I. 1.5, 8.5; P = 0.001) greater risk for p16 methylation in their tumors than controls. This increased probability for methylation approximated the 4-fold increase in relative risk for adenocarcinoma in this group of workers exposed to plutonium. In addition, a trend (P = 0.08) was seen for an increase in the number of genes methylated (
2 genes) with plutonium dose. Here we demonstrate that exposure to plutonium may elevate the risk for adenocarcinoma through specifically targeting the p16 gene for inactivation by promoter methylation.
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