Grant Number:	5R01CA207360-04 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:	2020

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.




Identification of a foetal epigenetic compartment in adult human kidney.
Authors: Wiencke J.K. , Zhang Z. , Koestler D.C. , Salas L.A. , Molinaro A.M. , Christensen B.C. , Kelsey K.T. .
Source: Epigenetics, 2021-03-30; , p. 1-21.
EPub date: 2021-03-30.
PMID: 33783321
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Authors: Eckel-Passow J.E. , Drucker K.L. , Kollmeyer T.M. , Kosel M.L. , Decker P.A. , Molinaro A.M. , Rice T. , Praska C.E. , Clark L. , Caron A. , et al. .
Source: Neuro-oncology, 2020-11-26; 22(11), p. 1602-1613.
PMID: 32386320
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Lack of association between modifiable exposures and glioma risk: a Mendelian randomization analysis.
Authors: Saunders C.N. , Cornish A.J. , Kinnersley B. , Law P.J. , Claus E.B. , Il'yasova D. , Schildkraut J. , Barnholtz-Sloan J.S. , Olson S.H. , Bernstein J.L. , et al. .
Source: Neuro-oncology, 2020-02-20; 22(2), p. 207-215.
PMID: 31665421
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Glioma risk associated with extent of estimated European genetic ancestry in African Americans and Hispanics.
Authors: Ostrom Q.T. , Egan K.M. , Nabors L.B. , Gerke T. , Thompson R.C. , Olson J.J. , LaRocca R. , Chowdhary S. , Eckel-Passow J.E. , Armstrong G. , et al. .
Source: International journal of cancer, 2020-02-01; 146(3), p. 739-748.
EPub date: 2019-04-22.
PMID: 30963577
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DNA methylation aging clocks: challenges and recommendations.
Authors: Bell C.G. , Lowe R. , Adams P.D. , Baccarelli A.A. , Beck S. , Bell J.T. , Christensen B.C. , Gladyshev V.N. , Heijmans B.T. , Horvath S. , et al. .
Source: Genome biology, 2019-11-25; 20(1), p. 249.
EPub date: 2019-11-25.
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Authors: Gervin K. , Salas L.A. , Bakulski K.M. , van Zelm M.C. , Koestler D.C. , Wiencke J.K. , Duijts L. , Moll H.A. , Kelsey K.T. , Kobor M.S. , et al. .
Source: Clinical epigenetics, 2019-08-27; 11(1), p. 125.
EPub date: 2019-08-27.
PMID: 31455416
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Absence of an embryonic stem cell DNA methylation signature in human cancer.
Authors: Zhang Z. , Wiencke J.K. , Koestler D.C. , Salas L.A. , Christensen B.C. , Kelsey K.T. .
Source: BMC cancer, 2019-07-19; 19(1), p. 711.
EPub date: 2019-07-19.
PMID: 31324166
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Genetic and molecular epidemiology of adult diffuse glioma.
Authors: Molinaro A.M. , Taylor J.W. , Wiencke J.K. , Wrensch M.R. .
Source: Nature reviews. Neurology, 2019 07; 15(7), p. 405-417.
EPub date: 2019-06-21.
PMID: 31227792
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Immune factors preceding diagnosis of glioma: a Prostate Lung Colorectal Ovarian Cancer Screening Trial nested case-control study.
Authors: Muskens I.S. , Zhou M. , Mccoy L. , Bracci P.M. , Hansen H.M. , Gauderman W.J. , Wiencke J.K. , Wrensch M.R. , Wiemels J.L. .
Source: Neuro-oncology advances, 2019 May-Dec; 1(1), p. vdz031.
EPub date: 2019-09-29.
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Cross-Cancer Pleiotropic Associations with Lung Cancer Risk in African Americans.
Authors: Jones C.C. , Bradford Y. , Amos C.I. , Blot W.J. , Chanock S.J. , Harris C.C. , Schwartz A.G. , Spitz M.R. , Wiencke J.K. , Wrensch M.R. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2019 04; 28(4), p. 715-723.
EPub date: 2019-03-20.
PMID: 30894353
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Authors: Eckel-Passow J.E. , Decker P.A. , Kosel M.L. , Kollmeyer T.M. , Molinaro A.M. , Rice T. , Caron A.A. , Drucker K.L. , Praska C.E. , Pekmezci M. , et al. .
Source: Neuro-oncology, 2019-03-18; 21(4), p. 451-461.
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Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2019 03; 28(3), p. 555-562.
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Authors: Ostrom Q.T. , Coleman W. , Huang W. , Rubin J.B. , Lathia J.D. , Berens M.E. , Speyer G. , Liao P. , Wrensch M.R. , Eckel-Passow J.E. , et al. .
Source: Neuro-oncology, 2019-01-01; 21(1), p. 71-82.
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Authors: Ostrom Q.T. , Kinnersley B. , Armstrong G. , Rice T. , Chen Y. , Wiencke J.K. , McCoy L.S. , Hansen H.M. , Amos C.I. , Bernstein J.L. , et al. .
Source: International journal of cancer, 2018-11-15; 143(10), p. 2359-2366.
EPub date: 2018-09-19.
PMID: 30152087
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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, 2018-10-01; 83(4), p. 709-718.
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Tracing human stem cell lineage during development using DNA methylation.
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Source: Genome research, 2018 09; 28(9), p. 1285-1295.
EPub date: 2018-08-02.
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Source: Genome biology, 2018-05-29; 19(1), p. 64.
EPub date: 2018-05-29.
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Source: Proceedings of the National Academy of Sciences of the United States of America, 2017-10-03; 114(40), p. 10743-10748.
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