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Article ; Online: Inherited polymorphisms in the Human Leukocyte Antigen Region modify the association between varicella-zoster virus antibody reactivity and glioma prognosis.

Francis, Stephen S / Guerra, Geno / Hansen, Helen M / Wendt, George / Kachuri, Linda / Wiencke, John K / Wrensch, Margaret

Neuro-oncology

2023 Volume 25, Issue 10, Page(s) 1910–1912

MeSH term(s)	Humans ; Herpesvirus 3, Human/genetics ; Glioma/genetics ; HLA Antigens ; Antibodies, Viral ; Prognosis
Chemical Substances	HLA Antigens ; Antibodies, Viral
Language	English
Publishing date	2023-08-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2028601-6
ISSN	1523-5866 ; 1522-8517
ISSN (online)	1523-5866
ISSN	1522-8517
DOI	10.1093/neuonc/noad122
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Article: Genome-wide Polygenic Risk Scores Predict Risk of Glioma and Molecular Subtypes.

Nakase, Taishi / Guerra, Geno / Ostrom, Quinn T / Ge, Tian / Melin, Beatrice / Wrensch, Margaret / Wiencke, John K / Jenkins, Robert B / Eckel-Passow, Jeanette E / Bondy, Melissa L / Francis, Stephen S / Kachuri, Linda

medRxiv : the preprint server for health sciences

2024

Abstract: Background: Polygenic risk scores (PRS) aggregate the contribution of many risk variants to provide a personalized genetic susceptibility profile. Since sample sizes of glioma genome-wide association studies (GWAS) remain modest, there is a need to find ...

Abstract	Background: Polygenic risk scores (PRS) aggregate the contribution of many risk variants to provide a personalized genetic susceptibility profile. Since sample sizes of glioma genome-wide association studies (GWAS) remain modest, there is a need to find efficient ways of capturing genetic risk factors using available germline data. Methods: We developed a novel PRS (PRS-CS) that uses continuous shrinkage priors to model the joint effects of over 1 million polymorphisms on disease risk and compared it to an approach (PRS-CT) that selects a limited set of independent variants that reach genome-wide significance (P<5×10 Results: PRS-CS was consistently more predictive than PRS-CT across glioma subtypes with an average increase in explained variance (R Conclusions: Our novel genome-wide PRS may improve the identification of high-risk individuals and help distinguish between prognostic glioma subtypes, increasing the potential clinical utility of germline genetics in glioma patient management.
Language	English
Publishing date	2024-01-11
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.10.24301112
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Article: Genetic predisposition to altered blood cell homeostasis is associated with glioma risk and survival.

Kachuri, Linda / Guerra, Geno A / Wendt, George A / Hansen, Helen M / Molinaro, Annette M / Bracci, Paige / McCoy, Lucie / Rice, Terri / Wiencke, John K / Eckel-Passow, Jeanette E / Jenkins, Robert B / Wrensch, Margaret / Francis, Stephen S

medRxiv : the preprint server for health sciences

2023

Abstract: Glioma is a highly fatal brain tumor comprised of molecular subtypes with distinct clinical trajectories. Observational studies have suggested that variability in immune response may play a role in glioma etiology. However, their findings have been ... ...

Abstract	Glioma is a highly fatal brain tumor comprised of molecular subtypes with distinct clinical trajectories. Observational studies have suggested that variability in immune response may play a role in glioma etiology. However, their findings have been inconsistent and susceptible to reverse causation due to treatment effects and the immunosuppressive nature of glioma. We applied genetic variants associated (p<5×10
Language	English
Publishing date	2023-10-16
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.15.23296448
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Article ; Online: Antibodies to varicella-zoster virus and three other herpesviruses and survival in adults with glioma.

Guerra, Geno / McCoy, Lucie / Hansen, Helen M / Rice, Terri / Molinaro, Annette M / Wiemels, Joseph L / Wiencke, John K / Wrensch, Margaret / Francis, Stephen S

Neuro-oncology

2023 Volume 25, Issue 6, Page(s) 1047–1057

Abstract: Background: Lifetime exposure to the varicella-zoster virus (VZV) has been consistently inversely associated with glioma risk, however, the relationship of VZV with survival in adults with glioma has not been investigated. In this study, we analyzed the ...

Abstract	Background: Lifetime exposure to the varicella-zoster virus (VZV) has been consistently inversely associated with glioma risk, however, the relationship of VZV with survival in adults with glioma has not been investigated. In this study, we analyzed the survival of adults with glioma in relation to their antibody measurements to 4 common herpes viral infections, including VZV, measured post-diagnosis. Methods: We analyzed IgG antibody measurements to VZV, cytomegalovirus (CMV), herpes simplex virus 1/2 (HSV), and Epstein-Barr virus (EBV) collected from 1378 adults with glioma diagnosed between 1991 and 2010. Blood was obtained a median of 3 months after surgery. Associations of patient IgG levels with overall survival were estimated using Cox models adjusted for age, sex, self-reported race, surgery type, dexamethasone usage at blood draw, and tumor grade. Models were stratified by recruitment series and meta-analyzed to account for time-dependent treatment effects. Results: VZV antibody seropositivity was associated with improved survival outcomes in adults with glioma (Hazard ratio, HR = 0.70, 95% Confidence Interval 0.54-0.90, P = .006). Amongst cases who were seropositive for VZV antibodies, survival was significantly improved for those above the 25th percentile of continuous reactivity measurements versus those below (HR = 0.76, 0.66-0.88, P = .0003). Antibody seropositivity to EBV was separately associated with improved survival (HR = 0.71, 0.53-0.96, P = .028). Antibody positivity to 2 other common viruses (CMV, HSV) was not associated with altered survival. Conclusions: Low levels of VZV or EBV antibodies are associated with poorer survival outcomes for adults with glioma. Differential immune response rather than viral exposure may explain these findings.
MeSH term(s)	Adult ; Humans ; Herpesvirus 3, Human ; Epstein-Barr Virus Infections ; Herpesvirus 4, Human ; Simplexvirus ; Cytomegalovirus ; Glioma ; Antibodies, Viral ; Cytomegalovirus Infections
Chemical Substances	Antibodies, Viral
Language	English
Publishing date	2023-01-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2028601-6
ISSN	1523-5866 ; 1522-8517
ISSN (online)	1523-5866
ISSN	1522-8517
DOI	10.1093/neuonc/noac283
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Article ; Online: Genetic and molecular epidemiology of adult diffuse glioma.

Molinaro, Annette M / Taylor, Jennie W / Wiencke, John K / Wrensch, Margaret R

Nature reviews. Neurology

2019 Volume 15, Issue 7, Page(s) 405–417

Abstract: The WHO 2007 glioma classification system (based primarily on tumour histology) resulted in considerable interobserver variability and substantial variation in patient survival within grades. Furthermore, few risk factors for glioma were known. ... ...

Abstract	The WHO 2007 glioma classification system (based primarily on tumour histology) resulted in considerable interobserver variability and substantial variation in patient survival within grades. Furthermore, few risk factors for glioma were known. Discoveries over the past decade have deepened our understanding of the molecular alterations underlying glioma and have led to the identification of numerous genetic risk factors. The advances in molecular characterization of glioma have reframed our understanding of its biology and led to the development of a new classification system for glioma. The WHO 2016 classification system comprises five glioma subtypes, categorized by both tumour morphology and molecular genetic information, which led to reduced misclassification and improved consistency of outcomes within glioma subtypes. To date, 25 risk loci for glioma have been identified and several rare inherited mutations that might cause glioma in some families have been discovered. This Review focuses on the two dominant trends in glioma science: the characterization of diagnostic and prognostic tumour markers and the identification of genetic and other risk factors. An overview of the many challenges still facing glioma researchers is also included.
MeSH term(s)	Biomarkers, Tumor ; Brain Neoplasms/classification ; Brain Neoplasms/genetics ; Brain Neoplasms/pathology ; Glioma/classification ; Glioma/genetics ; Glioma/pathology ; Humans
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2019-06-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2491514-2
ISSN	1759-4766 ; 1759-4758
ISSN (online)	1759-4766
ISSN	1759-4758
DOI	10.1038/s41582-019-0220-2
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Zs.A 6257: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MG 88: Show issues

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Article: Inherited genetics of adult diffuse glioma and polygenic risk scores-a review.

Eckel-Passow, Jeanette E / Lachance, Daniel H / Decker, Paul A / Kollmeyer, Thomas M / Kosel, Matthew L / Drucker, Kristen L / Slager, Susan / Wrensch, Margaret / Tobin, W Oliver / Jenkins, Robert B

Neuro-oncology practice

2022 Volume 9, Issue 4, Page(s) 259–270

Abstract: Knowledge about inherited and acquired genetics of adult diffuse glioma has expanded significantly over the past decade. Genomewide association studies (GWAS) stratified by histologic subtype identified six germline variants that were associated ... ...

Abstract	Knowledge about inherited and acquired genetics of adult diffuse glioma has expanded significantly over the past decade. Genomewide association studies (GWAS) stratified by histologic subtype identified six germline variants that were associated specifically with glioblastoma (GBM) and 12 that were associated with lower grade glioma. A GWAS performed using the 2016 WHO criteria, stratifying patients by
Language	English
Publishing date	2022-03-12
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2768945-1
ISSN	2054-2585 ; 2054-2577
ISSN (online)	2054-2585
ISSN	2054-2577
DOI	10.1093/nop/npac017
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Article ; Online: Pleiotropic

Walsh, Kyle M / Zhang, Chenan / Calvocoressi, Lisa / Hansen, Helen M / Berchuck, Andrew / Schildkraut, Joellen M / Bondy, Melissa L / Wrensch, Margaret / Wiemels, Joseph L / Claus, Elizabeth B

Neuro-oncology advances

2022 Volume 4, Issue 1, Page(s) vdac044

Abstract: Background: Risk of tumors of the breast, ovary, and meninges has been associated with hormonal factors and with one another. Genome-wide association studies (GWAS) identified a meningioma risk locus on 10p12 near previous GWAS hits for breast and ... ...

Abstract	Background: Risk of tumors of the breast, ovary, and meninges has been associated with hormonal factors and with one another. Genome-wide association studies (GWAS) identified a meningioma risk locus on 10p12 near previous GWAS hits for breast and ovarian cancers, raising the possibility of genetic pleiotropy. Methods: We performed imputation-based fine-mapping in three case-control datasets of meningioma (927 cases, 790 controls), female breast cancer (28 108 cases, 22 209 controls), and ovarian cancer (25 509 cases, 40 941 controls). Analyses were stratified by sex (meningioma), estrogen receptor (ER) status (breast), and histotype (ovarian), then combined using subset-based meta-analysis in ASSET. Lead variants were assessed for association with additional traits in UK Biobank to identify potential effect-mediators. Results: Two-sided subset-based meta-analysis identified rs7084454, an expression quantitative trait locus (eQTL) near the Conclusions: We identify a
Language	English
Publishing date	2022-04-15
Publishing country	England
Document type	Journal Article
ZDB-ID	3009682-0
ISSN	2632-2498 ; 2632-2498
ISSN (online)	2632-2498
ISSN	2632-2498
DOI	10.1093/noajnl/vdac044
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Article: Epidemiology.

Walsh, Kyle M / Ohgaki, Hiroko / Wrensch, Margaret R

Handbook of clinical neurology

2016 Volume 134, Page(s) 3–18

Abstract: More than 250,000 new cases of primary malignant brain tumors are diagnosed annually worldwide, 77% of which are gliomas. A small proportion of gliomas are caused by the inheritance of rare high-penetrance genetic variants or high-dose radiation. Since ... ...

Abstract	More than 250,000 new cases of primary malignant brain tumors are diagnosed annually worldwide, 77% of which are gliomas. A small proportion of gliomas are caused by the inheritance of rare high-penetrance genetic variants or high-dose radiation. Since 2009, inherited genetic variants in 10 regions near eight different genes have been consistently associated with glioma risk via genome-wide association studies. Most of these variants increase glioma risk by 20-40%, but two have higher relative risks. One on chromosome 8 increases risk of IDH-mutated gliomas sixfold and another that affects TP53 function confers a 2.5-fold increased risk of glioma. Functions of some of the other risk variants are known or suspected, but future research will determine functions of other risk loci. Recent progress also has been made in defining subgroups of glioma based on acquired alterations within tumors. Allergy history has been consistently associated with reduced glioma risk, though the mechanisms have not yet been clarified. Future studies will need to be large enough so that environmental and constitutive genetic risk factors can be examined within molecularly defined, etiologically homogeneous subgroups.
MeSH term(s)	Biomarkers, Tumor/genetics ; Brain Neoplasms/diagnosis ; Brain Neoplasms/epidemiology ; Brain Neoplasms/genetics ; Brain Neoplasms/therapy ; Humans ; Mutation/genetics ; Risk Factors
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2016-03-03
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ISSN	0072-9752
ISSN	0072-9752
DOI	10.1016/B978-0-12-802997-8.00001-3
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Article ; Online: Pre-surgery immune profiles of adult glioma patients.

Bracci, Paige M / Rice, Terri / Hansen, Helen M / Francis, Stephen S / Lee, Sean / McCoy, Lucie S / Shrestha, Pavan P / Warrier, Gayathri / Clarke, Jennifer L / Molinaro, Annette M / Taylor, Jennie W / Wiencke, John K / Wrensch, Margaret R

Journal of neuro-oncology

2022 Volume 159, Issue 1, Page(s) 103–115

Abstract: Introduction: Although immunosuppression is a known characteristic of glioma, no previous large studies have reported peripheral blood immune cell profiles prior to patient surgery and chemoradiation. This report describes blood immune cell ... ...

Abstract	Introduction: Although immunosuppression is a known characteristic of glioma, no previous large studies have reported peripheral blood immune cell profiles prior to patient surgery and chemoradiation. This report describes blood immune cell characteristics and associated variables prior to surgery among typical glioma patients seen at a large University practice. Methods: We analyzed pre-surgery blood samples from 139 glioma patients diagnosed with a new or recurrent grade II/III glioma (LrGG, n = 64) or new glioblastoma (GBM, n = 75) and 454 control participants without glioma. Relative cell fractions of CD4, CD8, B-cells, Natural Killer cells, monocytes, and neutrophils, were estimated via a validated deconvolution algorithm from blood DNA methylation measures from Illumina EPIC arrays. Results: Dexamethasone use at time of blood draw varied by glioma type being highest among patients with IDH wild-type (wt) GBM (75%) and lowest for those with oligodendroglioma (14%). Compared to controls, glioma patients showed statistically significant lower cell fractions for all immune cell subsets except for neutrophils which were higher (all p-values < 0.001), in part because of the higher prevalence of dexamethasone use at time of blood draw for IDHwt GBM. Patients who were taking dexamethasone were more likely to have a low CD4 count (< 200, < 500), increased neutrophils, low absolute lymphocyte counts, higher total cell count and higher NLR. Conclusion: We show that pre-surgery blood immune profiles vary by glioma subtype, age, and more critically, by use of dexamethasone. Our results highlight the importance of considering dexamethasone exposures in all studies of immune profiles and of obtaining immune measures prior to use of dexamethasone, if possible.
MeSH term(s)	Adult ; Brain Neoplasms/genetics ; Dexamethasone/therapeutic use ; Glioblastoma ; Glioma/genetics ; Humans ; Isocitrate Dehydrogenase/genetics ; Neoplasm Recurrence, Local
Chemical Substances	Dexamethasone (7S5I7G3JQL) ; Isocitrate Dehydrogenase (EC 1.1.1.41)
Language	English
Publishing date	2022-06-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	604875-4
ISSN	1573-7373 ; 0167-594X
ISSN (online)	1573-7373
ISSN	0167-594X
DOI	10.1007/s11060-022-04047-y
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Article ; Online: The immunogenetics of viral antigen response is associated with subtype-specific glioma risk and survival.

Guerra, Geno / Kachuri, Linda / Wendt, George / Hansen, Helen M / Mack, Steven J / Molinaro, Annette M / Rice, Terri / Bracci, Paige / Wiencke, John K / Kasahara, Nori / Eckel-Passow, Jeanette E / Jenkins, Robert B / Wrensch, Margaret / Francis, Stephen S

American journal of human genetics

2022 Volume 109, Issue 6, Page(s) 1105–1116

Abstract: Glioma is a highly fatal cancer with prognostically significant molecular subtypes and few known risk factors. Multiple studies have implicated infections in glioma susceptibility, but evidence remains inconsistent. Genetic variants in the human ... ...

Abstract	Glioma is a highly fatal cancer with prognostically significant molecular subtypes and few known risk factors. Multiple studies have implicated infections in glioma susceptibility, but evidence remains inconsistent. Genetic variants in the human leukocyte antigen (HLA) region modulate host response to infection and have been linked to glioma risk. In this study, we leveraged genetic predictors of antibody response to 12 viral antigens to investigate the relationship with glioma risk and survival. Genetic reactivity scores (GRSs) for each antigen were derived from genome-wide-significant (p < 5 × 10
MeSH term(s)	Antigens, Viral ; Epstein-Barr Virus Infections/complications ; Glioma/complications ; Glioma/genetics ; Herpesvirus 4, Human/genetics ; Humans ; Immunogenetics ; Multiple Sclerosis/genetics
Chemical Substances	Antigens, Viral
Language	English
Publishing date	2022-05-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	219384-x
ISSN	1537-6605 ; 0002-9297
ISSN (online)	1537-6605
ISSN	0002-9297
DOI	10.1016/j.ajhg.2022.04.011
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