Exposure to asbestos has long been associated with pleural mesothelioma. The mode of action of asbestos in inducing mesothelioma, however, remains to be completely described, and relatively little is known about the association of epigenetic inactivation of tumor suppressor genes with carcinogenic exposures. Asbestos is not a direct-acting mutagen, but is carcinogenic;as such, it is also known to persist in the lungs of exposed individuals. Our preliminary data has demonstrated that asbestos fiber burden is significantly associated with the number of tumor suppressor genes inactivated by epigenetic silencing and DNA methylation. We propose to expand this research by taking advantage of the newly developed International Mesothelioma Program (IMP) at the Brigham and Women's Hospital (BWH), where novel surgical treatment protocols have made possible for the first time investigation of tumor tissue from individuals with mesothelioma. We propose to test hypotheses positing that epigenetic inactivation of tumor suppressor genes, measured by assessing the DNA methylation profile, is associated with asbestos fiber type and burden. Further, we will test the hypothesis that the SV40 virus is involved in mesothelioma using a novel artifact resistant approach, and investigate the role of miRNAs in mesothelioma, asking if this might be a novel biomarker for this disease. Finally, we will test the hypothesis that survival in mesothelioma is associated with the individual molecular profile of the tumor. Our data will also be pooled with the expression profile data being generated at the BWH as part of the IMP, giving rise to a very rich repository of global genomic data for the exploratory analysis of the systems biology of malignant mesothelioma. In sum, we propose to continue to enroll and study patients referred to the BWH for new surgical treatments of this often fatal cancer. We will study the molecular character of their tumors, proposing that the character of the lesions in the tumor is associated with the nature of their asbestos exposure and well as with their response to treatment. Mesothelioma is a most often fatal cancer caused by asbestos exposure. We propose to study novel mechanisms of asbestos action in the body (including the inactivation and silencing of genes by induction of altered chromosome conformations), associating these with quantitative measures of asbestos exposure. This may help to explain, for example, why even small exposures (""""""""doses"""""""") of asbestos pose a fatal cancer risk.
| Langevin, Scott M; Kratzke, Robert A; Kelsey, Karl T (2015) Epigenetics of lung cancer. Transl Res 165:74-90 |
| Accomando, William P; Wiencke, John K; Houseman, E Andres et al. (2014) Quantitative reconstruction of leukocyte subsets using DNA methylation. Genome Biol 15:R50 |
| Watkins, Deborah J; Wellenius, Gregory A; Butler, Rondi A et al. (2014) Associations between serum perfluoroalkyl acids and LINE-1 DNA methylation. Environ Int 63:71-6 |
| Koestler, Devin C; Christensen, Brock C; Marsit, Carmen J et al. (2013) Recursively partitioned mixture model clustering of DNA methylation data using biologically informed correlation structures. Stat Appl Genet Mol Biol 12:225-40 |
| Watkins, Deborah J; Josson, Jyoti; Elston, Beth et al. (2013) Exposure to perfluoroalkyl acids and markers of kidney function among children and adolescents living near a chemical plant. Environ Health Perspect 121:625-30 |
| Houseman, Eugene Andres; Accomando, William P; Koestler, Devin C et al. (2012) DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics 13:86 |
| Accomando, William P; Wiencke, John K; Houseman, E Andres et al. (2012) Decreased NK cells in patients with head and neck cancer determined in archival DNA. Clin Cancer Res 18:6147-54 |
| Wiencke, John K; Accomando, William P; Zheng, Shichun et al. (2012) Epigenetic biomarkers of T-cells in human glioma. Epigenetics 7:1391-402 |
| Nelson, Heather H; Marsit, Carmen J; Christensen, Brock C et al. (2012) Key epigenetic changes associated with lung cancer development: results from dense methylation array profiling. Epigenetics 7:559-66 |
| Nelson, Heather H; Almquist, Lindsay M; LaRocca, Jessica L et al. (2011) The relationship between tumor MSLN methylation and serum mesothelin (SMRP) in mesothelioma. Epigenetics 6:1029-34 |
Showing the most recent 10 out of 27 publications
