The immunogenetics of viral antigen response is associated with subtype-specific glioma risk and survival

Guerra, Geno; Kachuri, Linda; Wendt, George A.; Hansen, Helen M.; Mack, Steven J.; Rice, Terri; Bracci, Paige M.; Wiencke, John K.; Kasahara, Nori; Eckel‐Passow, Jeanette E.; Jenkins, Robert B.; Wrensch, Margaret; Francis, Stephen

doi:10.1016/j.ajhg.2022.04.011

Cited by 7 publications

(5 citation statements)

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“…*Significant P values (FDR P < 0.05) carcinoma and cervical cancer [10]. The results of a previous research indicated that genetic predisposition toward increased seroreactivity to EBV ZEBRA was associated with a decreased overall glioma risk [44]. Despite previous studies, the association between viral infection and glioma incidence remains controversial [15].…”

Section: Discussionmentioning

confidence: 99%

Association between viral infections and glioma risk: a two-sample bidirectional Mendelian randomization analysis

Zhong,

Yang,

Zhang

et al. 2023

BMC Med

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Background Glioma is one of the leading types of brain tumor, but few etiologic factors of primary glioma have been identified. Previous observational research has shown an association between viral infection and glioma risk. In this study, we used Mendelian randomization (MR) analysis to explore the direction and magnitude of the causal relationship between viral infection and glioma. Methods We conducted a two-sample bidirectional MR analysis using genome-wide association study (GWAS) data. Summary statistics data of glioma were collected from the largest meta-analysis GWAS, involving 12,488 cases and 18,169 controls. Single-nucleotide polymorphisms (SNPs) associated with exposures were used as instrumental variables to estimate the causal relationship between glioma and twelve types of viral infections from corresponding GWAS data. In addition, sensitivity analyses were performed. Results After correcting for multiple tests and sensitivity analysis, we detected that genetically predicted herpes zoster (caused by Varicella zoster virus (VZV) infection) significantly decreased risk of low-grade glioma (LGG) development (OR = 0.85, 95% CI: 0.76–0.96, P = 0.01, FDR = 0.04). No causal effects of the other eleven viral infections on glioma and reverse causality were detected. Conclusions This is one of the first and largest studies in this field. We show robust evidence supporting that genetically predicted herpes zoster caused by VZV infection reduces risk of LGG. The findings of our research advance understanding of the etiology of glioma.

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Section: Discussionmentioning

confidence: 99%

Association between viral infections and glioma risk: a two-sample bidirectional Mendelian randomization analysis

Zhong,

Yang,

Zhang

et al. 2023

BMC Med

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“…Subtype information for the TCGA dataset ( IDH mutation, 1p/19q codeletion status, TERT mutation, primary diagnosis, grade) was downloaded from Ceccarelli et al 2016 21 . These datasets data quality control, imputation, and sample selection details have been previously described 22 .…”

Section: Methodsmentioning

confidence: 99%

The impact of germline variants in DNA repair pathways on survival and temozolomide toxicity in adults with glioma

Guerra,

Wendt,

McCoy

et al. 2023

Preprint

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Gliomas are highly fatal malignant brain tumors with prognostically relevant molecular subtypes. Genomic instability is a hallmark of cancer, including glioma, and DNA repair mechanisms are crucial to maintaining cell integrity. Temozolomide (TMZ), which utilizes specific DNA repair pathways in its mechanism of action, is one of the few standard-of-care drugs with a meaningful impact on IDH wildtype glioblastoma survival. However, its utility in non-glioblastomas is complicated by temozolomide-induced hypermutation. This study aims to identify if germline polymorphisms in DNA repair genes are associated with overall survival within glioma subtypes and if the polymorphisms modify survival in subjects treated with temozolomide. We utilized genotype data of 2078 adults with glioma collected through the UCSF Adult Glioma Study, Mayo Clinic, and TCGA, to study 1393 SNPs within 22 specific DNA repair genes on overall survival for all cases and for those with/without temozolomide exposure during first course of treatment. All models were fit separately for individuals grouped by major molecular subtypes. We identified four germline SNPs (within MLH1, MSH4, MSH3, and MUTYH) with a significant (p<0.00019) polygenic effect on survival, where the presence of at least one SNP decreased overall survival among grade 2 and 3 glioma cases with IDH mutated tumors (Hazard ratio per unit increase in number of present polymorphic sites, HR-PS=1.52, 95% confidence interval, CI: 1.26-1.83, p=1.3x10-5). In IDH mutant gliomas without somatic 1p/19q chromosomal arm codeletion, we identified a group of SNPs (in MSH4, ERCC2, and ERCC1) which showed a stepwise significant improvement on overall survival for each present germline polymorphism (HR-PS=0.67, 95% CI: 0.56-0.80, p=8.9x10-6). Within IDH mutant glioma cases, we also identified two mutations (rs1540354-T in MLH1, rs71636247-G in MSH3) which were significantly associated with decreased overall survival only amongst those with known temozolomide usage (HR-PS=2.23, 95% CI: 1.55-3.20, p=1.56x10-5), with no survival effect observed in the non-temozolomide group (HR=0.90, 95% CI: 0.63-1.28, p=0.56). One SNP in MSH2 was suggestively associated (p<0.005) with altered IDH wildtype glioblastoma response to temozolomide (rs149630102-T, HR=1.74, 95% CI: 1.27-2.39, p=0.00052). Suggestive associations for other glioma subtypes are also reported. We found evidence that germline polygenic alterations within DNA repair pathways may alter prognosis and potentially modulate temozolomide toxicity in adults with glioma. Further validation and functional work are warranted to assess if these markers can assist clinicians in individually tailoring therapeutic treatments for adults with glioma tumors.

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“…The prediction accuracy of PRS models were tested in the UK Biobank (UKB) 17,18 , a population-based cohort with 747 glioma cases (516 GBM, 146 non-GBM) and 412,556 controls. PRS models for molecular subtypes were tested in The Cancer Genome Atlas (TCGA) with controls from the Wellcome Trust Case Control Consortium (WTCCC), as described in Guerra et al 19 . The TCGA/WTCCC dataset consisted of 814 glioma cases (372 GBM, 442 non-GBM; 384 IDH wildtype, 384 IDH mutant) and 5,745 controls.…”

Section: Glioma Study Populationmentioning

confidence: 99%

Genome-wide Polygenic Risk Scores Predict Risk of Glioma and Molecular Subtypes

Nakase,

Guerra,

Ostrom

et al. 2024

Preprint

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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<5×10-8). PRS models were trained using GWAS results stratified by histological (10,346 cases, 14,687 controls) and molecular subtype (2,632 cases, 2,445 controls), and validated in two independent cohorts.Results: PRS-CS was consistently more predictive than PRS-CT across glioma subtypes with an average increase in explained variance (R2) of 21%. Improvements were particularly pronounced for glioblastoma tumors, with PRS-CS yielding larger effect sizes (odds ratio (OR)=1.93, P=2.0×10-54vs. OR=1.83, P=9.4×10-50) and higher explained variance (R2=2.82% vs. R2=2.56%). Individuals in the 95th percentile of the PRS-CS distribution had a 3-fold higher lifetime absolute risk of IDH mutant (0.63%) and IDH wildtype (0.76%) glioma relative to individuals with average PRS. PRS-CS also showed high classification accuracy for IDH mutation status among cases (AUC=0.895).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.

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The immunogenetics of viral antigen response is associated with subtype-specific glioma risk and survival

Cited by 7 publications

References 46 publications

Association between viral infections and glioma risk: a two-sample bidirectional Mendelian randomization analysis

Association between viral infections and glioma risk: a two-sample bidirectional Mendelian randomization analysis

The impact of germline variants in DNA repair pathways on survival and temozolomide toxicity in adults with glioma

Genome-wide Polygenic Risk Scores Predict Risk of Glioma and Molecular Subtypes

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