PRIM2: A Marker of MYC-driven Hyper-proliferation, Disease Progression, Tumor Aggressiveness and Poor Survival in Glioma Patients

Abstract

Background/Aim: Gliomas are the most prevalent brain tumors with metabolic alterations playing a pivotal role in disease progression. However, the precise coordination of metabolic alterations with tumor-promoting cellular mechanisms, leading to tumor initiation, progression, and aggressiveness, resulting in poor outcomes, remains poorly understood in gliomas. Materials and Methods: We conducted a metabolism-targeted differential gene expression analysis using glioma patients' expression profiling data from The Cancer Genome Atlas (TCGA) database. In addition, pathway enrichment analysis, gene set enrichment analysis (GSEA), transcription factor prediction, network construction, and correlation analyses were performed. Survival analyses were performed in R. All results were validated using independent GEO expression datasets. Results: Metabolism-targeted analysis identified 5 hits involved in diverse metabolic processes linking them to disease aggressiveness in gliomas. Subsequently, we established that cell cycle progression and hyper-proliferation are key drivers of tumor progression and aggressiveness in gliomas. One of the identified metabolic hits, DNA primase 2 (PRIM2), a gene involved in DNA replication was found directly associated with cell cycle progression in gliomas. Furthermore, our analysis indicated that PRIM2, along with other cell cycle-related genes, is under the control of and regulated by the oncogenic MYC transcription factor in gliomas. In addition, PRIM2 expression alone is enough to predict MYC-driven cell cycle progression and is associated with tumor progression, aggressive disease state, and poor survival in glioma patients. Conclusion: Our findings highlight PRIM2 as a marker of MYC-driven cell cycle progression and hyper-proliferation, disease onset and progression, tumor aggressiveness, and poor survival in glioma patients.Cancer, a multifaceted and formidable disease, spans a wide spectrum of malignancies and continually propels the boundaries of medical research (1). Among the intricate cancer types, gliomas emerge as a particularly complex and demanding subset of tumors. These primary brain tumors originate from neuroglial stem or progenitor cells, constituting 30% of all brain tumors and over 80% of malignant brain tumors (2). With an annual incidence rate of 6.6 cases per 100,000 individuals, gliomas exhibit a notable clinical heterogeneity, encompassing both slow-growing and highly aggressive forms, resulting in diverse disease progressions and clinical outcomes (3). Gliomas have been categorized into astrocytic, oligodendroglial, or ependymal tumors based on their histological characteristics and are assigned WHO grades 1-4 accordingly which indicate different degrees of malignancy (4). Tragically, glioblastoma (GBM), the exceptionally malignant form, accounts for half of newly diagnosed gliomas, with a median patient survival duration typically ranging from 14 to 17 months. Low-grade gliomas also carry the potential to progress into more aggressive 186