Biology subjects

Ostrom, Q. T.

Publications and source records attributed to Ostrom, Q. T..

5 recordsLinked to original sources

bioRxiv2026

Multi-Omics Study of Ancestry in Adults with Intracranial Cancers Glioma (MOSAIC)

BackgroundMost genomic studies of adult-type diffuse gliomas have focused on predominantly European ancestry populations, limiting the generalizability of molecular classifications and precision medicine approaches. We assembled a multi-institutional glioma cohort of diverse patients to investigate how germline ancestry, molecular subtypes, and mutational processes shape tumor biology and clinical outcomes. MethodsWe analyzed 1,102 adults with WHO 2021-classified diffuse gliomas (IDH-mutant, 1p/19q-codeleted oligodendroglioma; IDH-mutant astrocytoma; IDH-wildtype glioma) from seven U.S. institutions. Whole-exome sequencing (WES) of FFPE tumors identified somatic alterations and COSMIC SBS v3.2 mutational signatures. Genetic ancestry was estimated from WES using 1000 Genomes reference populations. Overall survival was assessed using Kaplan-Meier and multivariable models. ResultsThe cohort included 66.9% European (EUR), 21.1% Admixed American/Hispanic (AMR), 10.3% Admixed African (AFR), and 1.6% Asian (AS) ancestry. Survival followed expected molecular hierarchy (median overall survival: oligodendroglioma 15.7 years, astrocytoma 10.6 years, IDH-wildtype glioma 1.9 years). Within oligodendroglioma, AMR patients showed improved survival versus EUR (HR 0.67, 95% CI 0.48-0.94; p=0.011), with similar trends across subtypes. Somatic profiling confirmed canonical subtype-defining alterations and revealed higher ATRX alterations in AFR and AMR IDH-wildtype tumors compared with EUR. ATRX alterations were associated with improved survival only in AFR (p=0.003). Mutational signature analysis identified subtype-specific signatures, including therapy-associated signatures. Chemotherapy-related signatures were more frequent in EUR and AMR than in AFR. ConclusionsThis ancestrally diverse glioma cohort confirms established molecular classifications and identifies ancestry-associated differences in survival, somatic alterations, and mutational processes, indicating the critical need for broad representation to inform precision neuro-oncology. Key PointsO_LIA multi-institutional glioma cohort validates subtype and survival patterns across ancestries. C_LIO_LITherapy-associated mutational signatures differ by ancestry, suggesting distinct treatment-related mutational processes. C_LIO_LIAdmixed American patients show improved survival, particularly in oligodendroglioma. C_LI Importance of the StudyMost genomic studies of adult-type diffuse glioma have focused on populations of predominantly European ancestry which limits the ability to examine variation in tumor biology and clinical outcomes across populations. In this study, we assembled one of the largest ancestrally diverse cohorts of molecularly characterized adult diffuse gliomas, integrating germline ancestry inference with tumor whole-exome sequencing and mutational signature analysis. We confirm that established molecular classifications and survival hierarchies remain robust across ancestry groups. However, we also identified ancestry-associated differences in survival within specific tumor subtypes, higher ATRX alteration frequencies in African American and admixed American patients with IDH-wildtype tumors, and variation in therapy-associated mutational signatures across ancestry groups. These findings highlight the importance of incorporating population differences into genomic studies of glioma and provide a resource for future multi-ancestry investigations of glioma risk, tumor evolution, and treatment response, ultimately supporting more inclusive precision neuro-oncology.

bioinformatics↗

bioRxiv2026

Pharmacologic DPP-4 inhibition promotes CD8⁺ T cell metabolic fitness to enhance anti-tumor activity

Metabolic dysfunction is a hallmark of CD8+ T cell exhaustion in the tumor microenvironment. Thus, there is growing interest in developing strategies that enhance anti-tumor functions of CD8+ T cells via metabolic reprogramming. Here, we identify dipeptidyl peptidase 4 (DPP-4) as a previously unknown regulator of CD8+ T cell function and metabolism. We discovered that DPP-4 is upregulated in exhausted CD8+ T cells. Pharmacological inhibition of DPP-4 with the FDA-approved anti-diabetic drug sitagliptin transcriptionally and metabolically reprogrammed CD8+ T cells, increasing spare mitochondrial respiratory capacity, proliferation, cytotoxic mediator production, and antigen-specific cancer cell killing capability. The functional effects of sitagliptin were dependent on upregulation of glutamate decarboxylase 1 (GAD1), an enzyme that feeds glutamate into the tricarboxylic acid (TCA) cycle, highlighting a new role for GAD1 in CD8+ T cell respiration and proliferation. We found that systemic inhibition of DPP-4 in preclinical mouse glioblastoma (GBM) models prolongs survival in a CD8+ T cell-dependent manner, and retrospective clinical cohort analysis revealed better outcomes in GBM patients using DPP-4 inhibitors. Importantly, preconditioning of Chimeric Antigen Receptor (CAR) T-cells with DPP-4 inhibition enhanced their cytotoxicity, persistence, and therapeutic efficacy in pediatric GBM. Together, our findings provide mechanistic and biological rationale for repurposing readily accessible DPP-4 inhibitors to enhance anti-tumor CD8+ T cell responses.

immunology↗

bioRxiv2023

Intracranial tumors elicit systemic sympathetic hyperactivity that limits immunotherapeutic responses

Intracranial tumors present unique challenges for immunotherapy. These can include both local and systemic modes of immune suppression whose mechanistic underpinnings are incompletely understood. Here, we reveal that tumors harbored intracranially elicit systemic increases to circulating catecholamine levels, with the resultant chronic sympathetic hyperactivity driving T cell dysfunction and limiting immunotherapeutic success. Conversely, treatment with {beta}-adrenergic blockade increases NF-{kappa}B activity in immune cells, restores T cell polyfunctionality, modifies the tumor microenvironment, and licenses immune-based therapies in murine models of glioblastoma (GBM) to extend survival. Extended survival is also observed in GBM patients having received {beta}-adrenergic blockade, as well as in patients with melanoma and lung cancer brain metastases who received {beta}-blockade alongside concomitant immune checkpoint inhibition. While {beta}-blockade also impacts outcomes in the setting of extracranial disease, the benefits are especially pronounced in patients harboring intracranial disease burdens. These data suggest that sympathetic hyperactivity facilitates systemic immune dysfunction in the setting of intracranial tumors, specifically and advance a role for {beta}-adrenergic blockade in licensing immunotherapeutic responses within the intracranial compartment.

immunology↗

bioRxiv2017

Sex-specific genome-wide association study in glioma identifies new risk locus at 3p21.31 in females, and finds sex-differences in risk at 8q24.21

Incidence of glioma is approximately 50% higher in males. Previous analyses have examined exposures related to sex hormones in women as potential protective factors for these tumors, with inconsistent results. Previous glioma genome-wide association studies (GWAS) have not stratified by sex. Potential sex-specific genetic effects were assessed in autosomal SNPs and sex chromosome variants for all glioma, GBM and non-GBM patients using data from four previous glioma GWAS. Datasets were analyzed using sex-stratified logistic regression models and combined using meta-analysis. There were 4,831 male cases, 5,216 male controls, 3,206 female cases and 5,470 female controls. A significant association was detected at rs11979158 (7p11.2) in males only. Association at rs55705857 (8q24.21) was stronger in females than in males. A large region on 3p21.31 was identified with significant association in females only. The identified differences in effect of risk variants do not fully explain the observed incidence difference in glioma by sex.

epidemiology↗

bioRxiv2017

Sex-specific gene and pathway modeling of inherited glioma risk

BackgroundGenome-wide association studies (GWAS) have identified 25 risk variants for glioma, which explain ~30% of heritable risk. Most glioma histologies occur with significantly higher incidence in males. A sex-stratified analysis ide7ntified sex-specific glioma risk variants, and further analyses using gene- and pathway-based approaches may further elucidate risk variation by sex.\n\nMethodsResults from the Glioma International Case-Control Study were used as a testing set, and results from three GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for autosomal SNPs found to be nominally significant (p<0.01) in a previous meta-analysis and X chromosome SNPs with nominally significant association (p<0.01), three algorithms (Pascal, BimBam, and GATES) were used to generate gene-scores, and Pascal was used to generate pathway scores. Results were considered significant when p<3.3x10-6 in [2/3] algorithms.\n\nResults25 genes within five regions and 19 genes within six regions reached the set significance threshold in at least 2/3 algorithms in males and females, respectively. EGFR and RTEL1-TNFRSF6B were significantly associated with all glioma and glioblastoma in males only, and a female-specific association in TERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the Telomeres, Telomerase, Cellular Aging, and Immortality pathway in both males and females.\n\nConclusionsThese results suggest that there may be biologically relevant significant differences by sex in genetic risk for glioma. Additional gene- and pathway-based analyses may further elucidate the biological processes through which this risk is conferred.

epidemiology↗