Title: Epigenetic profiles, asbestos burden, and survival in pleural mesothelioma
Description: This thesis aimed to examine the relationships among aberrant epigenetic events, exposure to the carcinogenic mineral fiber asbestos, and patient outcomes in malignant pleural mesothelioma. Pleural mesothelioma is a rapidly fatal asbestos-associated malignancy with a median survival time of less than one year following diagnosis. Asbestos is the single most important contributor to the pathogenesis of pleural mesothelioma with approximately 80% of patients reporting a known exposure. First, the relationship between asbestos burden and survival in mesothelioma was examined using quantitative asbestos fiber burden measures in an effort to advance the understanding of the contribution of asbestos burden to disease prognosis. We found that lung tissue asbestos burden was a significant predictor of mesothelioma prognosis, and our data suggest that patient survival may be modified by susceptibility to this carcinogen. Next, an investigation of the relationship between epigenetic inactivation of six cell cycle control pathway genes and asbestos burden revealed that increasing asbestos burden was associated with an increased number of aberrant epigenetic silencing events, suggesting a novel tumorigenic mechanism of action of asbestos.

Lastly, we aimed to clarify the relations among gene-locus specific methylation and tumor status, asbestos burden, and disease survival with a comprehensive examination of aberrant epigenetic events at 1505 CpG loci associated with silencing of 803 cancer-related genes in pleural mesotheliomas and normal pleura. Classifying mesotheliomas and normal pleural samples based upon CpG methylation profile, we found that methylation profile classes differentiated tumor from normal pleura ( P < 0.0001). In addition, examining tumors demonstrated that methylation profile class membership significantly predicts lung tissue asbestos burden ( P < 0.03). Finally, we also found that both methylation class membership ( P < 0.01), and asbestos burden (HR = 1.4, 95% CI, 1.1-1.8) were significant predictors of patient survival in this disease. This work has demonstrated a role for asbestos as a significant contributor to aberrant epigenetic events in mesothelioma. Furthermore, this work has important clinical implications as we have shown that methylation profiles can differentiate diseased pleura from normal pleura, and that asbestos burden and methylation class membership are independent predictors of mesothelioma patient survival.