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

Brock C Christensen1, John J Godleski, Carmen J Marsit

  • 1Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA.

Carcinogenesis
|March 4, 2008
PubMed

Insights

Asbestos exposure is linked to malignant pleural mesothelioma (MPM) through tumor suppressor gene methylation. Higher asbestos body counts correlated with more methylated cell cycle genes in MPM patients.

Area of Science:

  • Oncology
  • Environmental Health
  • Molecular Biology

Background:

  • Malignant pleural mesothelioma (MPM) incidence is rising globally, with a known link to asbestos exposure.
  • The precise mechanisms by which asbestos causes MPM, particularly genetic alterations, remain largely unknown.
  • Promoter DNA CpG methylation leading to tumor suppressor gene inactivation is increasingly observed in MPM.

Purpose of the Study:

  • To investigate the relationship between asbestos exposure, patient demographics, tumor histology, and promoter methylation silencing of cell cycle control pathway tumor suppressor genes (TSGs) in MPM.
  • To examine six specific TSGs: APC, CCND2, CDKN2A, CDKN2B, HPPBP1, and RASSF1.

Main Methods:

  • A case series of 70 incident MPM cases was analyzed.
  • The study assessed promoter hypermethylation of six cell cycle control pathway TSGs.
  • Lung asbestos body burden was quantified and correlated with gene methylation status and patient characteristics.

Main Results:

  • A significantly higher lung asbestos body burden was observed when any of the studied cell cycle genes were methylated.
  • A significant trend showed increasing asbestos body counts with an increasing number of methylated cell cycle pathway genes (0, 1, or >1).
  • This association remained significant after controlling for age, gender, and tumor histology.

Conclusions:

  • The findings suggest a novel tumorigenic mechanism of action for asbestos exposure in MPM.
  • Asbestos exposure appears to influence the etiology and clinical course of MPM through the methylation of cell cycle pathway genes.
  • This research contributes to understanding the molecular pathways linking asbestos to mesothelioma development.

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