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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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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