Grant Details
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 |
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
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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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