A three ion channel genes-based signature predicts prognosis of primary glioblastoma patients and reveals a chemotherapy sensitive subtype

Abstract

Increasing evidence suggests that ion channels not only regulate electric signaling in excitable cells but also play important roles in the development of brain tumor. However, the roles of ion channels in glioma remain controversial. In the present study, we systematically analyzed the expression patterns of ion channel genes in a cohort of Chinese patients with glioma using RNAseq expression profiling. First, a molecular signature comprising three ion channel genes (KCNN4, KCNB1 and KCNJ10) was identified using Univariate Cox regression and two-tailed student's t test conducted in overall survival (OS) and gene expression. We assigned a risk score based on three ion channel genes to each primary Glioblastoma multiforme (pGBM) patient. We demonstrated that pGBM patients who had a high risk of unfavorable outcome were sensitive to chemotherapy. Next, we screened the three ion genes-based signature in different molecular glioma subtypes. The signature showed a Mesenchymal subtype and wild-type IDH1 preference. Gene ontology (GO) analysis for the functional annotation of the signature showed that patients with high-risk scores tended to exhibit the increased expression of proteins associated with apoptosis, immune response, cell adhesion and motion and vasculature development. Gene Set Enrichment Analysis (GSEA) results showed that pathways associated with negative regulation of programmed cell death, cell proliferation and locomotory behavior were highly expressed in the high-risk group. These results suggest that ion channel gene expression could improve the subtype classification in gliomas at the molecular level. The findings in the present study have been validated in two independent cohorts.

Identification of the potential biomarkers in patients with glioma: a weighted gene co-expression network analysis

“…CLIC1 might be related to the mechanism that the Metformin used to treat diabetes inhibit tumor proliferation ( 49 ). KCNB1 is a member of voltage-gated potassium channel, which cannot only regulate excitatory cell signals but also play a role in the occurrence of brain tumors ( 50 ). The moderate oxidation of this channel is thought to affect neurons by affecting synapses based on mouse experiments ( 51 ).…”

A TRPV2 interactome-based signature for prognosis in glioblastoma patients

“…Gene-based signatures, opposite to single gene expression, have been widely used to understand neoplasms [ 12 , 24 ]. A top-down supervised study based on the expression levels of ion channels in GBM identified a three-gene signature (KCNN4, KCNB1 and KCNJ10) significantly associated with OS of GBM [ 25 ]. Our main result is a proteomics interactome-based signature for GBM prognosis derived in a GBM patient cohort and validated in 2 independent cohorts.…”

Ion Channels as Therapeutic Targets in High Grade Gliomas

“…The expression of Kv channels is altered in many cancers, and their participation in neoplastic progression is well known [ 81 ]. A study of TGCA, Rembrandt and CGGA data sets identified three potassium channel genes KCNN4, KCNB1 and KCNJ10 that were found to hold a significant role in malignant progression of the tumour and were associated with overall survival in paediatric GBM (pGBM) [ 82 ]. In these samples, KCNN4 expression was upregulated, whereas the expression of KCNB1 and KCNJ10 was downregulated.…”

“…In these samples, KCNN4 expression was upregulated, whereas the expression of KCNB1 and KCNJ10 was downregulated. Based on this genetic signature, patients were classified into high risk (three gene signature) and low risk (no signature) and findings demonstrated that the pGBM patients that were identified as ‘high risk’ of poor outcome showed an increased sensitive to chemotherapy [ 82 ]. Finally, molecular analysis of the tumours revealed that this ion channel signature harnessed a mesenchymal subtype and wild-type IDH1 preference [ 82 ].…”