Radiation Research

Published by: Radiation Research Society

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Radiation Research 168(4):409-414. 2007
doi: 10.1667/RR0825.1

Radiation-Induced Lung Adenocarcinoma is Associated with Increased Frequency of Genes Inactivated by Promoter Hypermethylation

Christopher M. Lyona, Donna M. Klingea, Kieu C. Liechtya, Frederick D. Gentrya, Thomas H. Marcha, Terri Kangb, Frank D. Gillilandb, Galina Adamovac, Galina Rusinovac, Vitaliy Telnovc, and Steven A. Belinsky1,2a

aLovelace Respiratory Research Institute, Lung Cancer Program, Albuquerque, New Mexico 87108

bKeck School of Medicine, University of Southern California, Los Angeles, California 91105

cSouthern Ural Biophysics Institute, Ozyorsk, Russia

1011 Address for correspondence: Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM 87108-5127;

1022 Dr. Belinsky is a consultant to OncoMethylome Sciences, Inc. Under a licensing agreement between Lovelace Respiratory Research Institute and OncoMethylome Sciences, nested methylation-specific PCR was licensed to OncoMethylome Sciences, and the author is entitled to a share of the royalties received by the Institute from sales of licensed technology. The Institute, in accordance with its conflict-of-interest policies, is managing the terms of these arrangements

Abstract

Lyon, C. M., Klinge, D. M., Liechty, K. C., Gentry, F. D., March, T. H., Kang, T., Gilliland, F. D., Adamova, G., Rusinova, G., Telnov, V. and Belinsky, S. A. Radiation-Induced Lung Adenocarcinoma is Associated with Increased Frequency of Genes Inactivated by Promoter Hypermethylation. Radiat. Res. 168, 409–414 (2007).

Epigenetic inactivation of genes by promoter hypermethylation, a major mechanism in the initiation and progression of tobacco-induced cancer, has also been associated with lung cancer induced through environmental and occupational exposures. Our previous study of gene methylation in workers from the MAYAK nuclear enterprise identified a significantly higher prevalence for methylation of the p16 gene (CDKN2A) in adenocarcinomas from workers compared to tumors from non-worker controls. The purpose of this investigation was to determine whether genes in addition to p16 are “targeted” for silencing and whether overall gene methylation was more common in radiation-induced adenocarcinoma. A significant increase in the prevalence of methylation of GATA5 was seen in tumors from workers compared to tumors from controls. The prevalence for methylation of PAX5 β and H-cadherin did not differ in tumors from workers and controls. Evaluating the frequency for methylation of a five-gene panel revealed that 93% of adenocarcinomas from workers compared to 66% of tumors from controls were methylated for at least one gene. Moreover, a twofold increase was seen in the number of tumors methylated for three or more genes for tumors from workers compared to controls. Increased frequency for inactivation of genes by promoter hypermethylation and targeting of tumor suppressor genes such as GATA5 may be factors that contribute to the increased risk for lung cancer associated with radiation exposure.

Received: September 11, 2006; Accepted: June 29, 2007



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table

TABLE 1 Summary of Selected Demographics by Employment Status

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TABLE 2 Association between Promoter Methylation and Exposure to Internal and External Radiation as a Function of Workplace among MAYAK Workers

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TABLE 3 Aberrant Promoter Methylation in Adenocarcinomas from MAYAK Workers and Controls

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TABLE 4 Effect of Radiation Exposure on Multiplicity for Aberrant Methylation in Adenocarcinomas from Male MAYAK Workers Compared with Controls

 
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