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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
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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.

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Publications

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.
EPub date: 2014-03-12.
PMID: 24686037
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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, 2014-03-05; 15(3), p. R50.
EPub date: 2014-03-05.
PMID: 24598480
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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.
EPub date: 2013-11-18.
PMID: 24263140
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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.
EPub date: 2013-03-11.
PMID: 23482063
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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, 2013-03-05; 12(2), p. 225-40.
EPub date: 2013-03-05.
PMID: 23468465
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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; 7(12), p. 1391-402.
EPub date: 2012-10-29.
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; 18(22), p. 6147-54.
EPub date: 2012-09-26.
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; 7(6), p. 559-66.
EPub date: 2012-06-01.
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, 2012-05-08; 13, p. 86.
EPub date: 2012-05-08.
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.
EPub date: 2011-08-01.
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.
EPub date: 2011-07-01.
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; 17(11), p. 3579-89.
EPub date: 2011-04-19.
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; 103(2), p. 143-53.
EPub date: 2010-12-16.
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; 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; 26(20), p. 2578-85.
EPub date: 2010-08-16.
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; 103(6), p. 885-8.
EPub date: 2010-08-17.
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; 6(7), p. e1001043.
EPub date: 2010-07-29.
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; 70(14), p. 5686-94.
EPub date: 2010-06-29.
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, 2010-02-23; 5(2), p. e9372.
EPub date: 2010-02-23.
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; 25(16), p. 1999-2005.
EPub date: 2009-06-19.
PMID: 19542153
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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.
EPub date: 2009-08-14.
PMID: 19680444
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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; 69(15), p. 6315-21.
EPub date: 2009-07-28.
PMID: 19638575
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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; 69(1), p. 227-34.
PMID: 19118007
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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, 2008-09-09; 9, p. 365.
EPub date: 2008-09-09.
PMID: 18782434
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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.
EPub date: 2008-02-28.
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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