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

Carcinogenesis. 2008 Feb 28 [Epub ahead of print] [Link] [PDF Full Text]

Christensen BC, Godleski JJ, Marsit CJ, Houseman EA, Lopez-Fagundo CY, Longacker JL, Bueno R, Sugarbaker DJ, Nelson HH, Kelsey KT.

Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts 02115.


Malignant pleural mesothelioma (MPM) is a rapidly fatal tumor with increasing incidence world-wide 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 (TSG) 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.