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.

Loss of p15INK4bExpression in Colorectal Cancer is Linked to Ethnic Origin

“…Exposures to environmental toxicants and toxins might cause epigenetic changes (O'Hagan, 2013;Coppede et al, 2014;Senut et al, 2014) and it is clear that many different adverse environmental factors are likely to exist in the East compared to the West as discussed previously (Nieminen et al, 2012). Our data, together with the available literature (Belinsky et al, 2004;Marsit et al, 2006) suggest a link between environmental exposures, epigenetic changes and experimental models and large series of clinical samples.…”

Distinct Genetic and Epigenetic Signatures of Colorectal Cancers According to Ethnic Origin

“…Indeed, a recent study has shown that history of pesticide exposure and more frequently eating food directly from farms were significantly associated with a higher risk of colorectal carcinoma in Egypt (34). However, as the literature on this issue is still sparse (35)(36)(37), the hypothesis that environmental exposures could induce cancers through epigenetic changes remains to be confirmed in experimental models and large series of clinical samples. The Egyptian carcinomas showed MSI rates higher than the Western but MSI was not associated with TSGMP as seen in the Western material.…”

Multiplicity of abnormal promoter methylation in lung adenocarcinomas from smokers and never smokers

“…The most compelling support for DNA damage as an important modifier for methylation comes from studies in humans where increasing exposure to plutonium targeted the p16 gene for inactivation by methylation independent of cigarette smoke. 20 Both plutonium and radon result in the generation of ␣-particles that damage DNA. However, the deposition patterns for these 2 carcinogens differ, with plutonium and radon depositing largely within the peripheral and central lung, respectively.…”