Carcinogenesis Advance Access originally published online on January 23, 2004
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Leng, C. A. Stidley, R. Willink, A. Bernauer, K. Do, M. A. Picchi, X. Sheng, M. A. Frasco, D. Van Den Berg, F. D. Gilliland, et al. Double-Strand Break Damage and Associated DNA Repair Genes Predispose Smokers to Gene Methylation Cancer Res., April 15, 2008; 68(8): 3049 - 3056. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Herceg Epigenetics and cancer: towards an evaluation of the impact of environmental and dietary factors Mutagenesis, March 1, 2007; 22(2): 91 - 103. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Subramanian and R. Govindan Lung Cancer in Never Smokers: A Review J. Clin. Oncol., February 10, 2007; 25(5): 561 - 570. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Belinsky Silencing of genes by promoter hypermethylation: key event in rodent and human lung cancer Carcinogenesis, September 1, 2005; 26(9): 1481 - 1487. [Abstract] [Full Text] [PDF]
|
|