High prevalence of TP53 mutations is associated with poor survival and an EMT signature in gliosarcoma patients

Abstract

Gliosarcoma (GS) is a rare variant (2%) of glioblastoma (GBM) that poses clinical genomic challenges because of its poor prognosis and limited genomic information. To gain a comprehensive view of the genomic alterations in GS and to understand the molecular etiology of GS, we applied whole-exome sequencing analyses for 28 GS cases (6 blood-matched fresh-frozen tissues for the discovery set, 22 formalin-fixed paraffin-embedded tissues for the validation set) and copy-number variation microarrays for 5 blood-matched fresh-frozen tissues. TP53 mutations were more prevalent in the GS cases (20/28, 70%) compared to the GBM cases (29/90, 32%), and the GS patients with TP53 mutations showed a significantly shorter survival (multivariate Cox analysis, hazard ratio=23.9, 95% confidence interval, 2.87–199.63, P=0.003). A pathway analysis showed recurrent alterations in MAPK signaling (EGFR, RASGRF2 and TP53), phosphatidylinositol/calcium signaling (CACNA1s, PLCs and ITPRs) and focal adhesion/tight junction (PTEN and PAK3) pathways. Genomic profiling of the matched recurrent GS cases detected the occurrence of TP53 mutations in two recurrent GS cases, which suggests that TP53 mutations play a role in treatment resistance. Functionally, we found that TP53 mutations are associated with the epithelial–mesenchymal transition (EMT) process of sarcomatous components of GS. We provide the first comprehensive genome-wide genetic alternation profiling of GS, which suggests novel prognostic subgroups in GS patients based on their TP53 mutation status and provides new insight in the pathogenesis and targeted treatment of GS.

The Mutant p53-Driven Secretome Has Oncogenic Functions in Pancreatic Ductal Adenocarcinoma Cells

“…One of the most important proteins involved in DNA damage repair and apoptosis is the tumor suppressor protein p53 (TP53), which regulates a wide range of cellular biological processes to prevent tumor formation by killing or delaying the growth of neoplastic cells [ 5 ]. The importance of the p53 pathway in tumor suppression is also highlighted by the observation that TP53 mutations are associated to poor prognosis [ 6 ] and they are present in about half of all human cancers, reaching even ~75% of PDAC patients [ 7 , 8 ]. The great majority of p53 alterations are missense mutations that are localized in the DNA binding domain, which result in the expression of full-length mutant p53 isoforms [ 9 ].…”

Treatment-associated TP53 DNA-binding domain missense mutations in the pathogenesis of secondary gliosarcoma

“…This study clarifies previous work identifying a high frequency of TP53 mutations in both primary and secondary gliosarcomas [ 4 , 5 ]. Most recently, Cho et al sequenced TP53 to a coverage depth of approximately 120x in 28 FFPE gliosarcoma specimens, including 6 with matched normal samples, and observed an overall mutation frequency of 71% [ 6 ]. Synthesizing these studies with ours, we suggest that TP53 gain-of-function mutations are a key step in gliosarcoma pathogenesis.…”

“…Although most molecular studies of gliosarcoma have reported specimens with wildtype TP53 , an increasing sensitivity of mutation detection methods appears associated with increasing frequencies of mutation observed. Furthermore, wildtype p53 glioasarcoma exhibits an improved clinical prognosis compared to mutant p53 gliosarcoma, and may be a distinct molecular subtype despite similar histopathology [ 6 ]. Because TP53 gain-of-function mutations are also a hallmark of IDH-mutant astrocytomas and are frequently observed in IDH-wildtype GBM without any sarcomatoid features, they may not be sufficient for gliosarcoma pathogenesis.…”

“…Examination of TCGA whole exome sequencing (WES) data collected on low grade glioma and primary GBM reveals that missense mutations at codon 273 were detected in 29% of samples, compared to only 6% of p53-mutant GBM samples. Moreover, the same missense mutations were completely absent in a recent series of 25 gliosarcomas profiled by WES [ 6 ]. These differences may reflect the finding that missense mutations in various regions of the p53 DNA-binding domain (DBD) have different effects.…”

Gliosarcoma Protein - Protein Interaction Network Analysis and Gene Ontology

“…Treatment consists of surgical resection of the tumor followed by external radiotherapy or chemotherapy in some cases (4,5). Authors represented different genes involved in the disease as p53 mutant expression (6,7). Glial fibrillary acidic protein also reported as an diagnostic protein embedded in glioblastoma cells (8,9).…”