Asbestos exposure predicts cell cycle control gene promoter methylation in pleural mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is a rapidly fatal tumor with increasing incidence worldwide responsible for many thousands of deaths annually. Although there is a clear link between exposure to asbestos and mesothelioma, and asbestos is known to be both clastogenic and cytotoxic to mesothelial cells, the mechanisms of causation of MPM remain largely unknown. However, there is a rapidly emerging literature that describes inactivation of a diverse array of tumor suppressor genes (TSGs) via promoter DNA CpG methylation in MPM, although the etiology of these alterations remains unclear. We studied the relationships among promoter methylation silencing, asbestos exposure, patient demographics and tumor histology using a directed approach; examining six cell cycle control pathway TSGs in an incident case series of 70 MPMs. Promoter hypermethylation of APC, CCND2, CDKN2A, CDKN2B, HPPBP1 and RASSF1 were assessed. We observed significantly higher lung asbestos body burden if any of these cell cycle genes were methylated (P < 0.02), and there was a significant trend of increasing asbestos body counts as the number of methylated cell cycle pathway genes increased from 0 to 1 to >1 (P < 0.005). This trend of increasing asbestos body count and increasing number of methylated cell cycle pathway genes remained significant (P < 0.05) after controlling for age, gender and tumor histology. These data suggest a novel tumorigenic mechanism of action of asbestos and may contribute to the understanding of precisely how asbestos exposure influences the etiology and clinical course of malignant mesothelioma.

High Incidence of Somatic BAP1 Alterations in Sporadic Malignant Mesothelioma

“…For example, RASSF1 (Ras association -RalGDS/AF-6- domain family member 1) and E-cadherin promoter hypermethylation was detected in MM patients 42, 43 . High expression of DNA methyltransferases, DNMT1, was detected in pleural MM 44 .…”

XRCC1 and ERCC1 variants modify malignant mesothelioma risk: A case–control study

“…Moreover asbestos fibers may induce signal transduction (i.e. activation of NF-KB pathway [5]) and methylation of gene promoters [6].…”

Accumulation of radium in ferruginous protein bodies formed in lung tissue: association of resulting radiation hotspots with malignant mesothelioma and other malignancies

“…10) Possible linkages between asbestos fibers, the formation of the iron-rich protein, the formation of toxic reactive oxygen species (ROS), DNA damage in vitro and apoptosis resistance, have been discussed, proposed and suggested in relation to asbestos-mediated pathogenesis including malignant mesothelioma development. 11)–14) While the linkage is compelling, no specific mechanism appears to explain the development of malignant mesothelioma.…”