A four-gene signature-derived risk score for glioblastoma:prospects for prognostic and response predictive analyses

Objective: Glioblastoma(GBM) is the most common primary malignant brain tumor regulated by numerous genes, with poor survival outcomes and unsatisfactory response to therapy.Therefore, a robust, multi-gene signature-derived model is required to predict the prognosis and treatment response in GBM.Methods: Gene expression data of GBM from TCGA and GEO datasets were used to identify differentially expressed genes(DEGs)through DESeq2 or LIMMA methods.The DEGs were then overlapped and used for survival analysis by univariate and multivariate COX regression.Based on the gene signature of multiple survival-associated DEGs, a risk score model was established,and its prognostic and predictive role was estimated through Kaplan–Meier analysis and log-rank test.Gene set enrichment analysis(GSEA) was conducted to explore high-risk score-associated pathways.Western blot was used for protein detection.Results: Four survival-associated DEGs of GBM were identified: OSMR, HOXC10, SCARA3, and SLC39A10.The four-gene signature-derived risk score was higher in GBM than in normal brain tissues.GBM patients with a high-risk score had poor survival outcomes.The high-risk group treated with temozolomide chemotherapy or radiotherapy survived for a shorter duration than the low-risk group.GSEA showed that the high-risk score was enriched with pathways such as vasculature development and cell adhesion.Western blot confirmed that the proteins of these four genes were differentially expressed in GBM cells.Conclusions: The four-gene signature-derived risk score functions well in predicting the prognosis and treatment response in GBM and will be useful for guiding therapeutic strategies for GBM patients.

Elevated Kir2.1/nuclear N2ICD defines a highly malignant subtype of non-WNT/SHH medulloblastomas

Medulloblastoma(MB)is one of the most common childhood malignant brain tumors(WHO grade IV),traditionally divided into WNT,SHH,Group 3,and Group 4 subgroups based on the transcription profiles,somatic DNA alterations,and clinical outcomes.Unlike WNT and SHH subgroup MBs,Group 3 and Group 4 MBs have similar transcriptomes and lack clearly specific drivers and targeted therapeutic options.The recently revised WHO Classification of CNS Tumors has assigned Group 3 and 4 to a provisional non-WNT/SHH entity.In the present study,we demonstrate that Kir2.1,an inwardly-rectifying potassium channel,is highly expressed in non-WNT/SHH MBs,which promotes tumor cell invasion and metastasis by recruiting Adam10 to enhance S2 cleavage of Notch2 thereby activating the Notch2 signaling pathway.Disruption of the Notch2 pathway markedly inhibited the growth and metastasis of Kir2.1-overexpressing MB cell-derived xenograft tumors in mice.Moreover,Kir2.1^(high)/nuclear N2ICD^(high)MBs are associated with the significantly shorter lifespan of the patients.Thus,Kir2.1^(high)/nuclear N2ICD^(high)can be used as a biomarker to define a novel subtype of non-WNT/SHH MBs.Our findings are important for the modification of treatment regimens and the development of novel-targeted therapies for non-WNT/SHH MBs.