Combined expression of FOXO and Tribbles proteins predicts survival of glioma patients

Abstract

BackgroundGliomas, particularly high-grade variants such as glioblastoma, remain therapeutically challenging with poor survival outcomes. Current biomarkers inadequately stratify patients for therapy selection, monitoring, and early detection of progression. The FOXO transcription factors and Tribbles pseudokinases, key regulators of the PI3K/AKT pathway, have been implicated in cancer progression but their prognostic value in gliomas is unclear. The aim of this study was to determine whether transcriptional profiles of FOXO and Tribbles family members predict survival in glioma patients better than established biomarkers. MethodsUsing RNA-seq data from The Cancer Genome Atlas (TCGA, n = 705) and Chinese Glioma Genome Atlas (CGGA, n = 1018), along with microarray datasets (REMBRANDT, n = 552; Gravendeel, n = 268), we analyzed mRNA levels of FOXO1/3/4/6 and TRIB1/2/3. Survival analysis was performed via Kaplan-Meier curves, log-rank tests, and concordance indices. Gene expression differences across tumor grades and molecular subgroups were assessed using Students t-test. ResultsHigh FOXO1 and low FOXO3/4 mRNA levels, combined with elevated TRIB1/2/3 expression, formed a signature significantly associated with worse survival across all cohorts. This signature stratifies grade 4 gliomas, with a median survival difference of 4.5 months. Grade 4 tumors exhibited elevated FOXO1 and TRIB1/2/3 but reduced FOXO3/4 levels compared to lower-grade gliomas. ConclusionsThe FOXO/Tribbles transcriptional signature robustly predicts survival in glioma patients. These findings highlight its potential as a biomarker for patient stratification and a therapeutic target for high-grade gliomas. Key PointsO_LIFOXO/Tribbles mRNA signature predicts glioma survival status. Our analysis identifies a distinct transcriptional signature - characterized by high FOXO1 and TRIB1/2/3 levels along with low FOXO3 and FOXO4 - that consistently predicts poor prognosis across glioma cohorts. This FOXO/Tribbles signature demonstrates great prognostic power, particularly in grade 4 gliomas, providing an improved tool for risk stratification and clinical decision-making. C_LIO_LIHigh FOXO1 and Tribbles levels mark aggressive glioblastoma tumors. We show that elevated expression of FOXO1 and Tribbles pseudokinases is enriched in glioblastoma (GB) and grade 4 astrocytomas. These tumors, known for their aggressiveness and therapy resistance, are consistently associated with this unfavorable mRNA profile. This suggests a functional role for FOXO1 and Tribbles in glioma progression and highlights them as promising biomarkers and therapeutic targets. C_LIO_LIMulti-cohort validation (TCGA, CGGA) confirms prognostic robustness. The predictive FOXO/Tribbles expression pattern was validated across four large and independent datasets (TCGA, CGGA, REMBRANDT, and Gravendeel), demonstrating consistency despite differences in platform and population. This multi-cohort validation reinforces the robustness and generalizability of this transcriptional signature for predicting survival outcomes in glioma patients. C_LI Importance of the StudyGlioblastoma and high-grade gliomas have dismal prognoses, yet current biomarkers fail to adequately guide therapy. This study identifies a novel transcriptional signature - combining FOXO transcription factors and Tribbles pseudokinases - that robustly predicts survival in glioma patients stratifying aggressive tumors. Using multi-cohort validation (TCGA, CGGA, REMBRANDT), we demonstrate that elevated FOXO1 and Tribbles (TRIB1/2/3) levels, coupled with reduced FOXO3/4, correlate with poor outcomes in grade 4 gliomas. This signature is enriched in glioblastomas, highlighting its link to therapy resistance. Unlike prior studies focusing on individual proteins, our integrated analysis reveals their collective prognostic power, offering a pathway-specific biomarker for patient stratification. These findings provide a translational framework for targeting FOXO/Tribbles in precision oncology, addressing an urgent need for improved therapeutic strategies in neuro-oncology.