CRISPR-cas9 screening identified lethal genes enriched in Hippo kinase pathway and of predictive significance in primary low-grade glioma

Abstract

Background Low-grade gliomas (LGG) are a type of brain tumor that can be lethal, and it is essential to identify genes that are correlated with patient prognosis. In this study, we aimed to use CRISPR-cas9 screening data to identify key signaling pathways and develop a genetic signature associated with high-risk, low-grade glioma patients. Methods The study used CRISPR-cas9 screening data to identify essential genes correlated with cell survival in LGG. We used RNA-seq data to identify differentially expressed genes (DEGs) related to cell viability. Moreover, we used the least absolute shrinkage and selection operator (LASSO) method to construct a genetic signature for predicting overall survival in patients. We performed enrichment analysis to identify pathways mediated by DEGs, overlapping genes, and genes shared in the Weighted correlation network analysis (WGCNA). Finally, the study used western blot, qRT-PCR, and IHC to detect the expression of hub genes from signature in clinical samples. Results The study identified 145 overexpressed oncogenes in low-grade gliomas using the TCGA database. These genes were intersected with lethal genes identified in the CRISPR-cas9 screening data from Depmap database, which are enriched in Hippo pathways. A total of 19 genes were used to construct a genetic signature, and the Hippo signaling pathway was found to be the predominantly enriched pathway. The signature effectively distinguished between low- and high-risk patients, with high-risk patients showing a shorter overall survival duration. Differences in hub gene expression were found in different clinical samples, with the protein and mRNA expression of REP65 being significantly up-regulated in tumor cells. The study suggests that the Hippo signaling pathway may be a critical regulator of viability and tumor proliferation and therefore is an innovative new target for treating cancerous brain tumors, including low-grade gliomas. Conclusion Our study identified a novel genetic signature associated with high-risk, LGG patients. We found that the Hippo signaling pathway was significantly enriched in this signature, indicating that it may be a critical regulator of tumor viability and proliferation in LGG. Targeting the Hippo pathway could be an innovative new strategy for treating LGG.

Identification of TNFAIP6 as a reliable prognostic indicator of low-grade glioma

“…The incidence rate of LGG accounts for 20–30 % in adult with the median survival time of 5.6–13.3 years, which depends on the growth rate of the tumor, histopathological characteristics and the molecular phenotype [ [3] , [4] , [5] , [6] ]. Although significant progress has been made in recent years in the glioma, the long-term survival rate is still poor [ [7] , [8] , [9] ]. Therefore, it is urgent to probe out more meaningful prognostic monitoring indicators and determine novel effective treatment strategies for glioma.…”

A novel pipeline for prioritizing cancer type‐specific therapeutic vulnerabilities using DepMap identifies PAK2 as a target in head and neck squamous cell carcinomas

“…However, the published analyses of DepMap CRISPR screen data have mostly been conducted on a pan‐cancer basis and offer limited guidance for pursuing therapeutic vulnerabilities and predictive biomarkers specific to individual cancer types. Furthermore, analyses of individual cancer types in DepMap to date have narrowly focused on features distinguishing a malignancy of interest from the pan cancer dataset [ 7 , 8 , 9 ], predetermined biological processes [ 10 , 11 , 12 , 13 ], or developing prognostic models [ 14 , 15 , 16 , 17 ].…”