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

Abstract

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 beta 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.

Promoter hypermethylation may be an important mechanism of the transcriptional inactivation of ARRDC3, GATA5, and ELP3 in invasive ductal breast carcinoma

“…In previous studies, methylation of GATA5 was seen in many tumors including ductal breast cancer [11,[18][19][20][21][22][23]. Silencing of GATA5 gene expression as a result of promoter hypermethylation has been observed in lung, colorectal, renal cell, gastrointestinal, and ovarian cancers [20,22,36,37]. GATA5 promoter methylation in colorectal and renal cell carcinoma indicates a role of this gene in colorectal and renal cell carcinogenesis and most importantly as a potential biomarker for tumor progression [20,22].…”

Long-term epigenetic effects of exposure to low doses of 56Fe in the mouse lung

“…Tumor-suppressor gene-specific hypermethylation is a common feature of cancers, including radiation-induced lung adenocarcinomas [10]. It has been proposed that changes in individual gene DNA methylation are the driving events in tumorigenesis and can precede genetic mutations [19].…”

“…The role of epigenetic alterations in lung carcinogenesis has become increasingly recognized [9]. Studies have shown that radiation-induced lung adenocarcinomas are associated with an increased frequency of genes inactivated via promoter hypermethylation [10]. Additionally, p16 INK4A hypermethylation was detected in the lung tumors of workers exposed to plutonium [11].…”

Effects of ionizing radiation on DNA methylation: from experimental biology to clinical applications

“…Additional epigenetic evaluation of the MAYAK workers with lung adenocarcinomas demonstrated hypermethylation of GATA5 , a transcription regulatory protein needed for proper development and maintenance of cellular differentiation (Lyon et al, 2007). Analysis of the promoter methylation of a panel of 5 genes performed within this study has also shown that at least one of the genes was hypermethylated in 93% of adenocarcinomas from MAYAK workers, while hypermethylation of at least one gene was observed in only 66% of non-workers’ tumors.…”