Comprehensive analysis of Reverse Phase Protein Array data reveals characteristic unique proteomic signatures for glioblastoma subtypes

摘要

The most common and lethal type of intracranial tumors include the astrocytomas. Grade IV astrocytoma or Glioblastoma (GBM) is highly aggressive and treatment-refractory with a median survival of only 14 to 16 months. Molecular profiling of GBMs reveals a high degree of intra- and inter-tumoral heterogeneity, and hence it is important to understand the important signalling axes that get deregulated in different GBM subtypes to provide effective tailor-made therapies. In this study, we have carried out extensive analysis of Reverse Phase Protein Array (RPPA) data from TCGA cohort to develop protein signatures that define glioma grades or subtypes. The protein signatures that distinguished Grade II or III from GBM had largely overlapped, and pathway analysis revealed the positive enrichment of extracellular matrix proteins (ECM), MYC pathway, uPAR pathway and G2/M checkpoint genes in GBM. We also identified protein signatures for GBMs with genetic alterations (IDH mutation, p53 mutation, EGFR amplification or mutation, CDKN2A/CDKN2B deletion, and PTEN mutation) that occur at high frequency. G-CIMP positive GBM-specific protein signature showed a large similarity with IDH1-mutant protein signature, thus signifying the importance of IDH1 mutation driving the G-CIMP. Gene expression subtype analysis revealed an association of specific proteins to classical (EGFR and phosphor variants), mesenchymal (SERPINE1, TAZ, and Myosin-IIa_pS1943), neural (TUBA1B), and proneural (GSK3_pS9) types. Univariate Cox regression analysis identified several proteins showing significant correlation with GBM survival. Multivariate analysis revealed that IGFBP2 and RICTOR_pT1135 are independent predictors of survival. Overall, our analyses reveal that specific proteins are regulated in different glioma subtypes underscoring the importance of diverse signalling axes playing important role in the pathogenesis of glioma tumors.