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Grant Details

Grant Number: 5R01CA126939-05 Interpret this number
Primary Investigator: Kelsey, Karl
Organization: Brown University
Project Title: The Epidemiology of Molecular Alterations in Mesothelioma
Fiscal Year: 2012


Abstract

DESCRIPTION (provided by applicant): 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.



Publications

Cytomegalovirus infection in malignant pleural mesothelioma.
Authors: Hunter-Schlichting D. , Kelsey K.T. , Demmer R. , Patel M. , Bueno R. , Christensen B. , Fujioka N. , Kolarseri D. , Nelson H.H. .
Source: Plos One, 2021; 16(8), p. e0254136.
EPub date: 2021-08-12 00:00:00.0.
PMID: 34383785
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Epigenetics Of Lung Cancer
Authors: Langevin S.M. , Kratzke R.A. , Kelsey K.T. .
Source: Translational Research : The Journal Of Laboratory And Clinical Medicine, 2015 Jan; 165(1), p. 74-90.
PMID: 24686037
Related Citations

Associations Between Serum Perfluoroalkyl Acids And Line-1 Dna Methylation
Authors: Watkins D.J. , Wellenius G.A. , Butler R.A. , Bartell S.M. , Fletcher T. , Kelsey K.T. .
Source: Environment International, 2014 Feb; 63, p. 71-6.
PMID: 24263140
Related Citations

Quantitative Reconstruction Of Leukocyte Subsets Using Dna Methylation
Authors: Accomando W.P. , Wiencke J.K. , Houseman E.A. , Nelson H.H. , Kelsey K.T. .
Source: Genome Biology, 2014; 15(3), p. R50.
PMID: 24598480
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Recursively Partitioned Mixture Model Clustering Of Dna Methylation Data Using Biologically Informed Correlation Structures
Authors: Koestler D.C. , Christensen B.C. , Marsit C.J. , Kelsey K.T. , Houseman E.A. .
Source: Statistical Applications In Genetics And Molecular Biology, 2013 May; 12(2), p. 225-40.
PMID: 23468465
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Exposure To Perfluoroalkyl Acids And Markers Of Kidney Function Among Children And Adolescents Living Near A Chemical Plant
Authors: Watkins D.J. , Josson J. , Elston B. , Bartell S.M. , Shin H.M. , Vieira V.M. , Savitz D.A. , Fletcher T. , Wellenius G.A. .
Source: Environmental Health Perspectives, 2013 May; 121(5), p. 625-30.
PMID: 23482063
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Epigenetic Biomarkers Of T-cells In Human Glioma
Authors: Wiencke J.K. , Accomando W.P. , Zheng S. , Patoka J. , Dou X. , Phillips J.J. , Hsuang G. , Christensen B.C. , Houseman E.A. , Koestler D.C. , et al. .
Source: Epigenetics, 2012-12-01 00:00:00.0; 7(12), p. 1391-402.
PMID: 23108258
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Decreased NK cells in patients with head and neck cancer determined in archival DNA.
Authors: Accomando W.P. , Wiencke J.K. , Houseman E.A. , Butler R.A. , Zheng S. , Nelson H.H. , Kelsey K.T. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2012-11-15 00:00:00.0; 18(22), p. 6147-54.
EPub date: 2012-11-15 00:00:00.0.
PMID: 23014525
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Key Epigenetic Changes Associated With Lung Cancer Development: Results From Dense Methylation Array Profiling
Authors: Nelson H.H. , Marsit C.J. , Christensen B.C. , Houseman E.A. , Kontic M. , Wiemels J.L. , Karagas M.R. , Wrensch M.R. , Zheng S. , Wiencke J.K. , et al. .
Source: Epigenetics, 2012-06-01 00:00:00.0; 7(6), p. 559-66.
PMID: 22522909
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Dna Methylation Arrays As Surrogate Measures Of Cell Mixture Distribution
Authors: Houseman E.A. , Accomando W.P. , Koestler D.C. , Christensen B.C. , Marsit C.J. , Nelson H.H. , Wiencke J.K. , Kelsey K.T. .
Source: Bmc Bioinformatics, 2012; 13, p. 86.
PMID: 22568884
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The Relationship Between Tumor Msln Methylation And Serum Mesothelin (smrp) In Mesothelioma
Authors: Nelson H.H. , Almquist L.M. , LaRocca J.L. , Plaza S.L. , Lambert-Messerlian G.M. , Sugarbaker D.J. , Bueno R. , Godleski J.J. , Marsit C.J. , Christensen B.C. , et al. .
Source: Epigenetics, 2011 Aug; 6(8), p. 1029-34.
PMID: 21775819
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The Influence Of Aging, Environmental Exposures And Local Sequence Features On The Variation Of Dna Methylation In Blood
Authors: Langevin S.M. , Houseman E.A. , Christensen B.C. , Wiencke J.K. , Nelson H.H. , Karagas M.R. , Marsit C.J. , Kelsey K.T. .
Source: Epigenetics, 2011 Jul; 6(7), p. 908-19.
PMID: 21617368
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Global Hypomethylation Identifies Loci Targeted For Hypermethylation In Head And Neck Cancer
Authors: Poage G.M. , Houseman E.A. , Christensen B.C. , Butler R.A. , Avissar-Whiting M. , McClean M.D. , Waterboer T. , Pawlita M. , Marsit C.J. , Kelsey K.T. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2011-06-01 00:00:00.0; 17(11), p. 3579-89.
PMID: 21505061
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Dna Methylation, Isocitrate Dehydrogenase Mutation, And Survival In Glioma
Authors: Christensen B.C. , Smith A.A. , Zheng S. , Koestler D.C. , Houseman E.A. , Marsit C.J. , Wiemels J.L. , Nelson H.H. , Karagas M.R. , Wrensch M.R. , et al. .
Source: Journal Of The National Cancer Institute, 2011-01-19 00:00:00.0; 103(2), p. 143-53.
PMID: 21163902
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Pulmonary Endpoints (lung Carcinomas And Asbestosis) Following Inhalation Exposure To Asbestos
Authors: Mossman B.T. , Lippmann M. , Hesterberg T.W. , Kelsey K.T. , Barchowsky A. , Bonner J.C. .
Source: Journal Of Toxicology And Environmental Health. Part B, Critical Reviews, 2011; 14(1-4), p. 76-121.
PMID: 21534086
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Downregulated Micrornas In The Differential Diagnosis Of Malignant Pleural Mesothelioma
Authors: Gee G.V. , Koestler D.C. , Christensen B.C. , Sugarbaker D.J. , Ugolini D. , Ivaldi G.P. , Resnick M.B. , Houseman E.A. , Kelsey K.T. , Marsit C.J. .
Source: International Journal Of Cancer, 2010-12-15 00:00:00.0; 127(12), p. 2859-69.
PMID: 21351265
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Semi-supervised Recursively Partitioned Mixture Models For Identifying Cancer Subtypes
Authors: Koestler D.C. , Marsit C.J. , Christensen B.C. , Karagas M.R. , Bueno R. , Sugarbaker D.J. , Kelsey K.T. , Houseman E.A. .
Source: Bioinformatics (oxford, England), 2010-10-15 00:00:00.0; 26(20), p. 2578-85.
PMID: 20834038
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Sv40 Associated Mirnas Are Not Detectable In Mesotheliomas
Authors: Gee G.V. , Stanifer M.L. , Christensen B.C. , Atwood W.J. , Ugolini D. , Bonassi S. , Resnick M.B. , Nelson H.H. , Marsit C.J. , Kelsey K.T. .
Source: British Journal Of Cancer, 2010-09-07 00:00:00.0; 103(6), p. 885-8.
PMID: 20717113
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Breast cancer DNA methylation profiles are associated with tumor size and alcohol and folate intake.
Authors: Christensen B.C. , Kelsey K.T. , Zheng S. , Houseman E.A. , Marsit C.J. , Wrensch M.R. , Wiemels J.L. , Nelson H.H. , Karagas M.R. , Kushi L.H. , et al. .
Source: Plos Genetics, 2010-07-29 00:00:00.0; 6(7), p. e1001043.
EPub date: 2010-07-29 00:00:00.0.
PMID: 20686660
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Integrated Profiling Reveals A Global Correlation Between Epigenetic And Genetic Alterations In Mesothelioma
Authors: Christensen B.C. , Houseman E.A. , Poage G.M. , Godleski J.J. , Bueno R. , Sugarbaker D.J. , Wiencke J.K. , Nelson H.H. , Marsit C.J. , Kelsey K.T. .
Source: Cancer Research, 2010-07-15 00:00:00.0; 70(14), p. 5686-94.
PMID: 20587528
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The Correlation Between Rates Of Cancer And Autism: An Exploratory Ecological Investigation
Authors: Kao H.T. , Buka S.L. , Kelsey K.T. , Gruber D.F. , Porton B. .
Source: Plos One, 2010; 5(2), p. e9372.
PMID: 20186340
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Copy Number Variation Has Little Impact On Bead-array-based Measures Of Dna Methylation
Authors: Houseman E.A. , Christensen B.C. , Karagas M.R. , Wrensch M.R. , Nelson H.H. , Wiemels J.L. , Zheng S. , Wiencke J.K. , Kelsey K.T. , Marsit C.J. .
Source: Bioinformatics (oxford, England), 2009-08-15 00:00:00.0; 25(16), p. 1999-2005.
PMID: 19542153
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Differentiation of lung adenocarcinoma, pleural mesothelioma, and nonmalignant pulmonary tissues using DNA methylation profiles.
Authors: Christensen B.C. , Marsit C.J. , Houseman E.A. , Godleski J.J. , Longacker J.L. , Zheng S. , Yeh R.F. , Wrensch M.R. , Wiemels J.L. , Karagas M.R. , et al. .
Source: Cancer Research, 2009-08-01 00:00:00.0; 69(15), p. 6315-21.
EPub date: 2009-08-01 00:00:00.0.
PMID: 19638575
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Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context.
Authors: Christensen B.C. , Houseman E.A. , Marsit C.J. , Zheng S. , Wrensch M.R. , Wiemels J.L. , Nelson H.H. , Karagas M.R. , Padbury J.F. , Bueno R. , et al. .
Source: Plos Genetics, 2009 Aug; 5(8), p. e1000602.
PMID: 19680444
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Epigenetic Profiles Distinguish Pleural Mesothelioma From Normal Pleura And Predict Lung Asbestos Burden And Clinical Outcome
Authors: Christensen B.C. , Houseman E.A. , Godleski J.J. , Marsit C.J. , Longacker J.L. , Roelofs C.R. , Karagas M.R. , Wrensch M.R. , Yeh R.F. , Nelson H.H. , et al. .
Source: Cancer Research, 2009-01-01 00:00:00.0; 69(1), p. 227-34.
PMID: 19118007
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Asbestos Exposure Predicts Cell Cycle Control Gene Promoter Methylation In Pleural Mesothelioma
Authors: Christensen B.C. , Godleski J.J. , Marsit C.J. , Houseman E.A. , Lopez-Fagundo C.Y. , Longacker J.L. , Bueno R. , Sugarbaker D.J. , Nelson H.H. , Kelsey K.T. .
Source: Carcinogenesis, 2008 Aug; 29(8), p. 1555-9.
PMID: 18310086
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Asbestos Burden Predicts Survival In Pleural Mesothelioma
Authors: Christensen B.C. , Godleski J.J. , Roelofs C.R. , Longacker J.L. , Bueno R. , Sugarbaker D.J. , Marsit C.J. , Nelson H.H. , Kelsey K.T. .
Source: Environmental Health Perspectives, 2008 Jun; 116(6), p. 723-6.
PMID: 18560526
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Model-based Clustering Of Dna Methylation Array Data: A Recursive-partitioning Algorithm For High-dimensional Data Arising As A Mixture Of Beta Distributions
Authors: Houseman E.A. , Christensen B.C. , Yeh R.F. , Marsit C.J. , Karagas M.R. , Wrensch M. , Nelson H.H. , Wiemels J. , Zheng S. , Wiencke J.K. , et al. .
Source: Bmc Bioinformatics, 2008; 9, p. 365.
PMID: 18782434
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