Abstract
Glioblastoma multiforme (GBM) is the most common and devastating type of primary brain tumor, with a median survival time of only 15 months. Having a clinically applicable genetic biomarker would lead to a paradigm shift in precise diagnosis, personalized therapeutic decisions, and prognostic prediction for GBM. Radiogenomic profiling connecting radiological imaging features with molecular alterations will offer a noninvasive method for genomic studies of GBM. To this end, we analyzed over 3800 glioma and GBM cases across four independent datasets. The Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases were employed for RNA-Seq analysis, whereas the Ivy Glioblastoma Atlas Project (Ivy-GAP) and The Cancer Imaging Archive (TCIA) provided clinicopathological data. The Clinical Proteomic Tumor Analysis Consortium Glioblastoma Multiforme (CPTAC-GBM) was used for proteomic analysis. We identified a simple three-gene transcriptome signature—SOCS3, VEGFA, and TEK—that can connect GBM’s overall prognosis with genes’ expression and simultaneously correlate radiographical features of perfusion imaging with SOCS3 expression levels. More importantly, the rampant development of neovascularization in GBM offers a promising target for therapeutic intervention. However, treatment with bevacizumab failed to improve overall survival. We identified SOCS3 expression levels as a potential selection marker for patients who may benefit from early initiation of angiogenesis inhibitors.
Highlights
Despite intensive research efforts and continuous advances in treatment options, glioblastoma multiforme (GBM) remains the most common and aggressive type of tumor in the central nervous system (CNS) in adults [1]
The distribution of VEGFA expression was mainly found in the pseudopalisading cells around necrosis (PAN) area, whereas suppressor of cytokine signaling 3 (SOCS3) expression was primarily identified in the PAN and microvascular proliferation (MVP) areas (Figure 1A)
These patterns of distribution were further confirmed by in situ hybridization (ISH) data showing higher SOCS3 expression in perivascular and PAN areas, whereas VEGFA expression was mainly found in the PAN area (Figure 1B)
Summary
Despite intensive research efforts and continuous advances in treatment options, glioblastoma multiforme (GBM) remains the most common and aggressive type of tumor in the central nervous system (CNS) in adults [1]. Molecular profiling (World Health Organization [WHO] grades II–III) has classified lower-grade gliomas (LLGs) into three distinct molecular subgroups: isocitrate dehydrogenase (IDH) wildtype, IDH-mutated with 1p/19q codeletion, and IDH-mutated without 1p/19q codeletion [3]. Such molecular profiling for GBM is still lacking [4]. Recent investigation revealed that elevated expression levels of the substrate-binding protein suppressor of cytokine signaling 3 (SOCS3) in the CRL5 complex are correlated with chemo- and radioresistance in GBM [12,13,14]. The underlying molecular functional mechanisms of SOCS3 in GBM progression remain largely unknown
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