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Grant Details

Grant Number: 5R01CA207360-02 Interpret this number
Primary Investigator: Wiencke, John
Organization: University Of California, San Francisco
Project Title: Immune Epigenetic Biomarkers of Survival in Glioma Epidemiology
Fiscal Year: 2018
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Abstract

Project Summary/Abstract Gliomas are devastating central nervous tumors that are associated with an immunosuppressive network impacting the tumor microenvironment, bone marrow and the peripheral blood compartments. The development of novel biomarkers of cancer immunity have not kept pace with breakthroughs in our understanding of cancer-associated inflammation and its relationship with abnormal hematopoiesis and the production of myeloid related suppressor cells (MDSC). This gap in our understanding is a recognized high priority in the new era of cancer immunotherapy. The Cancer Moonshot blue ribbon panel recommended as a key actionable goal ?to develop approaches to overcome an obstructive, immune-suppressive tumor environment in both children and adults?. Our project addresses this important goal by developing and testing a highly innovative approach for measuring immunosuppression in glioma patients. In Aim 1 we will augment our validated epigenetic bioinformatic approach for leukocyte profiles to include both granulocytic and monocytic MDSCs. We use specific DNA methylation changes as quantitative markers of immune cell types. In Aim 2 we will then assess the predictive value of methylation generated immune profiles (CD4, CD8, T-cells, B- cells, NK, monocytes, neutrophils, gMDSC, mMDSC) in glioma patient progression and survival. Patients will be carefully selected from the UCSF Adult Glioma Study to represent key molecular genetic subtypes of glioma using three diagnostic gene mutations (IDH, TERT, 1p19q deletion). We then will validate the blood immune profiles in an independent population of glioma patients from the Mayo Clinic. We will also augment Aim 2 by oversampling an uncommon and poorly understood subset of glioma patients whose tumors do not contain any of the three cardinal mutations (i.e. triple negative glioma). To explore the relationship of blood and tumor immune profiles we will apply genome wide methylation assay to tumors in Aim 3 from patients with matched blood samples from UCSF. We will then replicate tumor blood correlations within the Mayo Clinic patient population. This comprehensive program will develop new tools to characterize the destructive immune suppression in glioma patients. Our epigenetic immune approach is highly flexible and cost effective and will provide a major advance for evaluating immune factors in glioma treatment and outcomes.

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Publications

Tracing human stem cell lineage during development using DNA methylation.
Authors: Salas L.A. , Wiencke J.K. , Koestler D.C. , Zhang Z. , Christensen B.C. , Kelsey K.T. .
Source: Genome Research, 2018-08-02 00:00:00.0; , .
EPub date: 2018-08-02 00:00:00.0.
PMID: 30072366
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An optimized library for reference-based deconvolution of whole-blood biospecimens assayed using the Illumina HumanMethylationEPIC BeadArray.
Authors: Salas L.A. , Koestler D.C. , Butler R.A. , Hansen H.M. , Wiencke J.K. , Kelsey K.T. , Christensen B.C. .
Source: Genome Biology, 2018-05-29 00:00:00.0; 19(1), p. 64.
EPub date: 2018-05-29 00:00:00.0.
PMID: 29843789
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Sex-specific glioma genome-wide association study identifies new risk locus at 3p21.31 in females, and finds sex-differences in risk at 8q24.21.
Authors: Ostrom Q.T. , Kinnersley B. , Wrensch M.R. , Eckel-Passow J.E. , Armstrong G. , Rice T. , Chen Y. , Wiencke J.K. , McCoy L.S. , Hansen H.M. , et al. .
Source: Scientific Reports, 2018-05-09 00:00:00.0; 8(1), p. 7352.
EPub date: 2018-05-09 00:00:00.0.
PMID: 29743610
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Influence of obesity-related risk factors in the aetiology of glioma.
Authors: Disney-Hogg L. , Sud A. , Law P.J. , Cornish A.J. , Kinnersley B. , Ostrom Q.T. , Labreche K. , Eckel-Passow J.E. , Armstrong G.N. , Claus E.B. , et al. .
Source: British Journal Of Cancer, 2018 Apr; 118(7), p. 1020-1027.
EPub date: 2018-03-13 00:00:00.0.
PMID: 29531326
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Immunomethylomics: A Novel Cancer Risk Prediction Tool.
Authors: Kelsey K.T. , Wiencke J.K. .
Source: Annals Of The American Thoracic Society, 2018 Apr; 15(Supplement_2), p. S76-S80.
PMID: 29676642
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Impact of atopy on risk of glioma: a Mendelian randomisation study.
Authors: Disney-Hogg L. , Cornish A.J. , Sud A. , Law P.J. , Kinnersley B. , Jacobs D.I. , Ostrom Q.T. , Labreche K. , Eckel-Passow J.E. , Armstrong G.N. , et al. .
Source: Bmc Medicine, 2018-03-15 00:00:00.0; 16(1), p. 42.
EPub date: 2018-03-15 00:00:00.0.
PMID: 29540232
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Mendelian randomisation study of the relationship between vitamin D and risk of glioma.
Authors: Takahashi H. , Cornish A.J. , Sud A. , Law P.J. , Kinnersley B. , Ostrom Q.T. , Labreche K. , Eckel-Passow J.E. , Armstrong G.N. , Claus E.B. , et al. .
Source: Scientific Reports, 2018-02-05 00:00:00.0; 8(1), p. 2339.
EPub date: 2018-02-05 00:00:00.0.
PMID: 29402980
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Probing the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in gliomas: A phase 2 study of everolimus for recurrent adult low-grade gliomas.
Authors: Wahl M. , Chang S.M. , Phillips J.J. , Molinaro A.M. , Costello J.F. , Mazor T. , Alexandrescu S. , Lupo J.M. , Nelson S.J. , Berger M. , et al. .
Source: Cancer, 2017-12-01 00:00:00.0; 123(23), p. 4631-4639.
EPub date: 2017-07-31 00:00:00.0.
PMID: 28759109
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Seizure Outcome After Surgical Resection of Insular Glioma.
Authors: Wang D.D. , Deng H. , Hervey-Jumper S.L. , Molinaro A.A. , Chang E.F. , Berger M.S. .
Source: Neurosurgery, 2017-11-08 00:00:00.0; , .
EPub date: 2017-11-08 00:00:00.0.
PMID: 29126238
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Improved Survival with Decreased Wait Time to Surgery in Glioblastoma Patients Presenting with Seizure.
Authors: Flanigan P.M. , Jahangiri A. , Kuang R. , Truong A. , Choi S. , Chou A. , Rick J.W. , Chang S.M. , Molinaro A.M. , McDermott M.W. , et al. .
Source: Neurosurgery, 2017-11-01 00:00:00.0; 81(5), p. 824-833.
PMID: 28541497
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Non-additive and epistatic effects of HLA polymorphisms contributing to risk of adult glioma.
Authors: Zhang C. , de Smith A.J. , Smirnov I.V. , Wiencke J.K. , Wiemels J.L. , Witte J.S. , Walsh K.M. .
Source: Journal Of Neuro-oncology, 2017 Nov; 135(2), p. 237-244.
EPub date: 2017-07-18 00:00:00.0.
PMID: 28721485
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Germline polymorphisms in myeloid-associated genes are not associated with survival in glioma patients.
Authors: Jacobs D.I. , Liu Y. , Gabrusiewicz K. , Tsavachidis S. , Armstrong G.N. , Zhou R. , Wei J. , Ivan C. , Calin G. , Molinaro A.M. , et al. .
Source: Journal Of Neuro-oncology, 2017-09-30 00:00:00.0; , .
EPub date: 2017-09-30 00:00:00.0.
PMID: 28965162
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Germline Genetic Variants and Lung Cancer Survival in African Americans.
Authors: Jones C.C. , Bush W.S. , Crawford D.C. , Wenzlaff A.S. , Schwartz A.G. , Wiencke J.K. , Wrensch M.R. , Blot W.J. , Chanock S.J. , Grogan E.L. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2017 Aug; 26(8), p. 1288-1295.
EPub date: 2017-06-15 00:00:00.0.
PMID: 28619829
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Identifying Voxels at Risk for Progression in Glioblastoma Based on Dosimetry, Physiologic and Metabolic MRI.
Authors: Anwar M. , Molinaro A.M. , Morin O. , Chang S.M. , Haas-Kogan D.A. , Nelson S.J. , Lupo J.M. .
Source: Radiation Research, 2017 09; 188(3), p. 303-313.
EPub date: 2017-07-19 00:00:00.0.
PMID: 28723274
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Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1.
Authors: Mazor T. , Chesnelong C. , Pankov A. , Jalbert L.E. , Hong C. , Hayes J. , Smirnov I.V. , Marshall R. , Souza C.F. , Shen Y. , et al. .
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 2017-10-03 00:00:00.0; 114(40), p. 10743-10748.
EPub date: 2017-09-15 00:00:00.0.
PMID: 28916733
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