Vault proteins as prognostic biomarkers and therapeutic targets in lower-grade gliomas.

Abstract

2082 Background: Vault proteins, including MVP, VPARP, and TEP1, are components of the vault complex, and are involved in drug resistance, DNA repair, and cell survival. However, their role in low-grade gliomas (LGG) remains unclear. This study explored the expression and prognostic significance of LGG with the aim of uncovering their potential as biomarkers. Methods: Using the TCGA-LGG cohort, Kaplan Meier (KM) and uni/multivariate Cox proportional hazards regression (CPH) analyses were performed using R 4.3.3, and hazard ratios (HR) with 95% confidence intervals (CI) were reported. MVP, TEP1, and VPARP (PARP4) expression levels were further stratified according to the LGG subtype. Multi-gene KM plots were generated to stratify overall survival (OS), progression-free survival (PFS), and disease-specific survival (DSS) using gene set variation analysis (GSVA) scores. “ImmuCellAI” algorithm was utilized for immune infiltration analysis. The GDSC and CTRP databases were used for drug sensitivity analyses. Results: As indicated by KM and univariate CPH analyses, MVP (hazard ratio [HR] = 1.5, 95% CI: 1.3-1.8), TEP1 (HR = 1.7, 95% CI: 1.4-2.0), and VPARP (HR = 1.6, 95% CI: 1.3-1.9) predicted poor OS. MVP, in multivariate CPH model adjusted to tumor grade and histology, remained significant (HR = 1.37, 95% CI: 1.14-1.70). The expression of MVP, TEP1, and VPARP was the highest in astrocytomas and the lowest in oligodendrogliomas (p < 0.05), with oligoastrocytomas in between. 3-gene KM signature analysis revealed a negative association between higher GSVA scores and OS, PFS, and DSS (log-rank p < 0.01) (Table). Immune infiltration analysis indicated positive macrophage, Th1, Th2, and dendritic cell infiltration with higher GSVA (derived from MVP, TEP1, and VPARP) (r > 0.40, FDR < 0.05) and negative infiltration of naive CD8+ and neutrophils (r < -0.30, FDR < 0.05). Drug analysis revealed vincristine resistance with higher MVP expression (r = 0.44, FDR < 0.001). Conclusions: MVP, TEP1, and VPARP were associated with poor survival outcomes and distinct immune infiltration patterns in LGG. These findings highlight the potential of vault proteins as biomarkers and therapeutic targets for LGG. Univariate Cox proportional hazards ratios for the different survival types for GSVA scores of the three major proteins of the vault (MVP, TEP1, and VPARP). Survival type Hazard Ratio Cox P value Logrank P value Higher risk of death OS 1.7 <0.001 24E-2.03 Higher GSVA PFS 1.43 0.01 9.09E-03 Higher GSVA DSS 1.75 <0.001 2.18E-03 Higher GSVA