Carcinogenesis Advance Access published online on January 23, 2004
Carcinogenesis, doi:10.1093/carcin/bgh096
© 2004 by Oxford University Press
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CARCINOGENESIS
1 Lovelace Respiratory Research Institute, Lung Cancer Program, 2425 Ridgecrest Dr. SE, Albuquerque, NM 87108
* Corresponding author. E-mail: sbelinsk{at}LRRI.org.
Received 30 October 2003
; revised 12 January 2004
; accepted 13 January 2004
Lung cancer from radon or 239plutonium exposure has been linked to
lung cancer, p16 methylation, radiation
Plutonium targets the p16 gene for inactivation by promoter hypermethylation in human lung adenocarcinoma
2 Keck School of Medicine, University of Southern California, Los Angeles, CA 91105
3 Southern Ural Biophysics Institute, Ozyorsk, Russia
-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 nonworker controls. Lung adenocarcinomas were examined from workers and nonworker controls for methylation of the CDKN2A (p16), O6-methylguanine-DNA methyltransfease (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 to nonworker controls. Stratification of plutonium exposure into textiles 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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