Abstract
Intertumoral molecular heterogeneity in glioblastoma identifies four major subtypes based on expression of molecular markers. Among them, the two clinically interrelated subtypes, proneural and mesenchymal, are the most aggressive with proneural liable for conversion to mesenchymal upon therapy. Using two patient-derived novel primary cell culture models (MTA10 and KW10), we developed a minimal but unique four-gene signature comprising genes vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor B (VEGF-B) and angiopoietin 1 (ANG1), angiopoietin 2 (ANG2) that effectively segregated the proneural (MTA10) and mesenchymal (KW10) glioblastoma subtypes. The cell culture preclassified as mesenchymal showed elevated expression of genes VEGF-A, VEGF-B and ANG1, ANG2 as compared to the other cell culture model that mimicked the proneural subtype. The differentially expressed genes in these two cell culture models were confirmed by us using TCGA and Verhaak databases and we refer to it as a minimal multigene signature (MMS). We validated this MMS on human glioblastoma tissue sections with the use of immunohistochemistry on preclassified (YKL-40 high or mesenchymal glioblastoma and OLIG2 high or proneural glioblastoma) tumor samples (n = 30). MMS segregated mesenchymal and proneural subtypes with 83% efficiency using a simple histopathology scoring approach (p = 0.008 for ANG2 and p = 0.01 for ANG1). Furthermore, MMS expression negatively correlated with patient survival. Importantly, MMS staining demonstrated spatiotemporal heterogeneity within each subclass, adding further complexity to subtype identification in glioblastoma. In conclusion, we report a novel and simple sequencing-independent histopathology-based biomarker signature comprising genes VEGF-A, VEGF-B and ANG1, ANG2 for subtyping of proneural and mesenchymal glioblastoma.
Highlights
Gliomas account for ~30% of all brain and central nervous system tumors and 80% of all malignant brain tumors
Using two patient-derived novel primary cell culture models (MTA10 and KW10), we developed a minimal but unique four-gene signature comprising genes vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor B (VEGF-B) and angiopoietin 1 (ANG1), angiopoietin 2 (ANG2) that effectively segregated the proneural (MTA10) and mesenchymal (KW10) glioblastoma subtypes
KW10 cultures consisted of small, flattened cells that were morphologically uniform, whereas MTA10 cultures consisted of elongated cells that appeared predominantly neuronal (Figure 1A)
Summary
Gliomas account for ~30% of all brain and central nervous system tumors and 80% of all malignant brain tumors. The regulatory landscape of glioblastoma has led to its categorization into four major molecular subtypes: neural, classical, proneural, and mesenchymal [5,6,7]. Each of these subtypes harbor unique genomic and epigenomic regulatory features and are clinically independent and manifest various prognostic significances. Spatiotemporal heterogeneity is manifested at a single-cell level and causes coexistence of multiple molecular subtypes within a single glioblastoma tumor often yielding chimeric glioblastoma cell clones [2, 8]. The possibility of subtype switch in glioblastoma induced by chemotherapy and the high levels of intertumoral heterogeneity necessitates accurate identification of tumor subtypes in glioblastoma [9, 10]. The various data sets generated by TCGA analyzed through genetic, gene expression, and DNA methylation signatures have led to the identification of divergent glioma subtypes elucidated on the basis of the status of the IDH1 gene, codeletion of chromosome arm 1p/19q, and TERT promoter status [11]
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