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Grant Details

Grant Number: 5R01CA207360-05 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: 2021


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.



Publications

Interactions of Age and Blood Immune Factors and Non-Invasive Prediction of Glioma Survival.
Authors: Molinaro A.M. , Wiencke J.K. , Warrier G. , Koestler D.C. , Chunduru P. , Lee J.Y. , Hansen H.M. , Lee S. , Anguiano J. , Rice T. , et al. .
Source: Journal of the National Cancer Institute, 2021-10-01; , .
EPub date: 2021-10-01.
PMID: 34597382
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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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Adult diffuse glioma GWAS by molecular subtype identifies variants in D2HGDH and FAM20C.
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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Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.
Authors: Zhang Y.D. , Hurson A.N. , Zhang H. , Choudhury P.P. , Easton D.F. , Milne R.L. , Simard J. , Hall P. , Michailidou K. , Dennis J. , et al. .
Source: Nature communications, 2020-07-03; 11(1), p. 3353.
EPub date: 2020-07-03.
PMID: 32620889
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Association of Maximal Extent of Resection of Contrast-Enhanced and Non-Contrast-Enhanced Tumor With Survival Within Molecular Subgroups of Patients With Newly Diagnosed Glioblastoma.
Authors: Molinaro A.M. , Hervey-Jumper S. , Morshed R.A. , Young J. , Han S.J. , Chunduru P. , Zhang Y. , Phillips J.J. , Shai A. , Lafontaine M. , et al. .
Source: JAMA oncology, 2020-04-01; 6(4), p. 495-503.
PMID: 32027343
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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.
PMID: 31767039
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Systematic evaluation and validation of reference and library selection methods for deconvolution of cord blood DNA methylation data.
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.
PMID: 31807733
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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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Using germline variants to estimate glioma and subtype risks.
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.
PMID: 30624711
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Aspirin, NSAIDs, and Glioma Risk: Original Data from the Glioma International Case-Control Study and a Meta-analysis.
Authors: Amirian E.S. , Ostrom Q.T. , Armstrong G.N. , Lai R.K. , Gu X. , Jacobs D.I. , Jalali A. , Claus E.B. , Barnholtz-Sloan J.S. , Il'yasova D. , 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 03; 28(3), p. 555-562.
EPub date: 2018-11-27.
PMID: 30482874
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Sex-specific gene and pathway modeling of inherited glioma risk.
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.
PMID: 30124908
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Age-specific genome-wide association study in glioblastoma identifies increased proportion of 'lower grade glioma'-like features associated with younger age.
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.
PMID: 29126238
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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 09; 28(9), p. 1285-1295.
EPub date: 2018-08-02.
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; 19(1), p. 64.
EPub date: 2018-05-29.
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; 8(1), p. 7352.
EPub date: 2018-05-09.
PMID: 29743610
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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 04; 15(Suppl 2), p. S76-S80.
PMID: 29676642
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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 04; 118(7), p. 1020-1027.
EPub date: 2018-03-13.
PMID: 29531326
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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; 16(1), p. 42.
EPub date: 2018-03-15.
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; 8(1), p. 2339.
EPub date: 2018-02-05.
PMID: 29402980
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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, 2018 Jan; 136(1), p. 33-39.
EPub date: 2017-09-30.
PMID: 28965162
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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; 123(23), p. 4631-4639.
EPub date: 2017-07-31.
PMID: 28759109
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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.
PMID: 28721485
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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; 81(5), p. 824-833.
PMID: 28541497
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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; 114(40), p. 10743-10748.
EPub date: 2017-09-15.
PMID: 28916733
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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.
PMID: 28723274
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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 08; 26(8), p. 1288-1295.
EPub date: 2017-06-15.
PMID: 28619829
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