Changes of major genes related to cellular senescence in glioma

Senescent glioma cells shape the clinical profile of gliomas, playing a key role in clinical outcome and response to therapy. The aim of this study was to analyze the frequency and type of alterations in genes characterized as markers of cellular senescence in different types and grades of gliomas. We analyzed 3425 glioma samples using data from the cBioPortal for Cancer Genomics. After querying 88 genes involved in senescence-associated secretory phenotype (SASP), we selected and studied in detail the 10 most frequently altered ones: TP53 , CDKN2A , EGFR , ATM , TNFRSF1A , IGFBP7 , TNFRSF11B , TP53BP1 , HGF and SERPINE1 . Data analyses included determining the frequency of mutations and copy number alteration(CNA). Additionally, transcript levels, methylation patterns, and survivals were queried for each gene through GlioVis and GEPIA portals, while STRING provided protein network. Our results show that the majority of the studied genes were changed in high-grade gliomas. Genes TP53 , CDKN2A , and EGFR were the most frequently altered ones. TP53, TP53BP1, ATM, HGF were mostly hit by mutations, while TNFRSF1A, TNFRSF11B, IGFBP7, SERPINE1, EGFR by amplifications. CDKN2A was predominantly deleted. The alterations of CDKN2A, EGFR, and IGFBP7 were significantly more frequent in the high grade (HGG) group, while TP53 and TNFRSF11B in the low grade (LGG) group. Patients harboring alterations in SASP genes had significantly shorter overall survival. The expression levels of TP53, TNFRSF1A, TNFRSF11B , IGFBP7, HGF, SERPINE1 and EGFR were significantly higher in HGG, while ATM and TP53BP1 transcript was falling in higher grades. All genes showed significant expression differences according to IDH1 status. mRNA expression levels were associated to levels of methylation for genes ATM , TP53 , and TP53BP1 . Our findings highlight the importance of cellular senescence in glioma progression, and may provide insights for the development of future senomorphics therapies.