title: Plutonium targets the p16 gene for inactivation by promoter hypermethylation in human lung adenocarcinoma.
abstract: Lung cancer from radon or (239)plutonium 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), O(6)-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 (> or =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.
authors.affiliation: Lovelace Respiratory Research Institute, Lung Cancer Program, 2425 Ridgecrest Drive SE, Albuquerque, NM 87108, USA. sbelinsk@lrri.org
authors.forename: Steven A
authors.initials: SA
authors.lastname: Belinsky
authors.forename: Donna M
authors.initials: DM
authors.lastname: Klinge
authors.forename: Kieu C
authors.initials: KC
authors.lastname: Liechty
authors.forename: Thomas H
authors.initials: TH
authors.lastname: March
authors.forename: Terri
authors.initials: T
authors.lastname: Kang
authors.forename: Frank D
authors.initials: FD
authors.lastname: Gilliland
authors.forename: Natalie
authors.initials: N
authors.lastname: Sotnic
authors.forename: Galina
authors.initials: G
authors.lastname: Adamova
authors.forename: Galina
authors.initials: G
authors.lastname: Rusinova
authors.forename: Vitaliy
authors.initials: V
authors.lastname: Telnov
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D019175:DNA Methylation; D020868:Gene Silencing; D019942:Genes, p16 / Q000528:radiation effects*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D011005:Plutonium / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011829:Radiation Dosage
chemical_list: D011005:Plutonium