Plutonium targets the p16 gene for inactivation by promoter hypermethylation in human lung adenocarcinoma

Authors: Steven A. Belinsky¹; Donna M. Klinge¹; Kieu C. Liechty¹; Thomas H. March¹; Terri Kang²; Frank D. Gilliland²; Natalie Sotnic³; Galina Adamova³; Galina Rusinova³; Vitaliy Telnov³

Source: Carcinogenesis, Volume 25, Number 6, June 2004 , pp. 1063-1067(5)

Publisher: Oxford University Press

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Abstract:

Lung cancer from radon or ²³⁹plutonium exposure has been linked to alpha

-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.

Document Type: Research article

DOI: http://dx.doi.org/10.1093/carcin/bgh096

Affiliations: 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

Publication date: 2004-06-01

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Carcinogenesis is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal will publish papers that warrant prompt publication in the areas of Cancer Biology, Molecular Epidemiology and Cancer Prevention, and Carcinogenesis.

Plutonium targets the p16 gene for inactivation by promoter hypermethylation in human lung adenocarcinoma

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