2643 - Brain Protein I3 (BRI3) Predicts Disease Fate in Glioblastoma
Presenter(s)
I. C. Ogobuiro1, S. M. Welford2, and M. Bredel3; 1Department of Radiation Oncology, University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL, 2Case Western Reserve University, Cleveland, OH, 3Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, United States
Purpose/Objective(s): Genome-wide characterization has illuminated the molecular complexity of human gliomas. Genetic alterations help predict the clinical behavior of gliomas, but variability persists. Accordingly, there is a need to expanding molecular signatures that refine prognostication. The Brain Protein I3 (BRI3) gene, localized on chromosome 7, is associated with high-grade glioma, yielding the highest hazard ratio among all high-risk genes in an in-silico glioma model. Given GBM's known chromosome 7 gain and BRI3's chromosomal location, we hypothesized that gene dosage gains and overexpression serve as prognostic biomarkers.
Materials/Methods: We used the Rembrandt (n=461 patients) and TCGA low-grade glioma (LGG) and GBM (n=1,148 patients) databases for multi-omic analyses. RNA sequencing (Illumina HiSeq) and DNA methylation profiles (Illumina 450K) were analyzed in a combined LGG and GBM cohort, with high/low expression and hyper/hypomethylation defined by median values. CNV analysis (GISTIC 2.0) classified 2 copies as gene-copy neutral and >2 as gene dosage gain. Somatic mutation data (SNPs/INDELs) were derived from whole-exome sequencing to decipher IDH-wt and IDH-mutant gliomas. Univariate and adjusted Cox models, Kaplan-Meier estimates, and receiver operating characteristic (ROC) curve analysis were performed.
Results: Of 461 Rembrandt patients, 47.29% were GBM, 31.89% astrocytoma, 14.53% oligodendroglioma, and 6.29% normal brain. Among 1,148 TCGA LGG/GBM patients, 551 had complete molecular and clinical data, with 28% IDH-wt status, 49% MGMT hypermethylation, and 36.66% BRI3 gene dosage gains. BRI3 expression was significantly higher in GBM, grade IV tumors, IDH-wt, and mesenchymal subtypes. Among the IDH-wt cases, 75% showed BRI3 gene dosage gains with significantly elevated mRNA expression. EGFR, co-amplified in 80% of IDH-wt cases, did not affect survival (25.27 vs. 17.90 months, p = 0.346). Conversely, BRI3 gene dosage gain correlated with worse survival (79.3 vs. 17.93 mo, p = 0.001), as did BRI3 high vs. low expression (17.90 vs. 25.27 months, p = 0.015) and MGMT hypermethylation (25.27 vs. 18.63 mo, p = 0.021). Univariate analysis linked patient age (HR: 2.858 [1.781–4.586], p < 0.001), MGMT hypermethylation (HR: 2.632 [1.307–5.301], p = 0.007), BRI3 high expression (HR: 1.938 [1.131–3.320], p = 0.016) and BRI3 gene dosage gain (HR: 2.504 [1.425–4.398], p = 0.001) to worse OS. Adjusted multivariate Cox regression confirmed BRI3 gene dosage gain, age, and MGMT methylation as independent OS predictors in IDH-wt cases. ROC analysis revealed stronger prognostic performance for BRI3 gene dosage gain than MGMT hypermethylation (AUC: 0.737 vs. 0.616, p< 0.001) in IDH-wt cases.
Conclusion: Elevated BRI3 gene dosage and expression portend poor prognosis and could be incorporated into models predicting disease fate in GBM.