Journal Article

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

Steven A. Belinsky, Donna M. Klinge, Kieu C. Liechty, Thomas H. March, Terri Kang, Frank D. Gilliland, Natalie Sotnic, Galina Adamova, Galina Rusinova and Vitaliy Telnov

in Carcinogenesis

Volume 25, issue 6, pages 1063-1067
Published in print June 2004 | ISSN: 0143-3334
Published online June 2004 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/bgh096
Plutonium targets the p16 gene for inactivation by promoter hypermethylation in human lung adenocarcinoma

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Lung cancer from radon or 239plutonium exposure has been linked to α-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.

Keywords: DAP-K, death associated protein kinase; LET, linear energy transfer; MGMT, O6-methylguanine-DNA methyltransferase; Pu, 239plutonium; p16, CDKN2A; RASSF1A, Ras effector homolog 1

Journal Article.  3814 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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