Identification of genetic alterations in childhood and adolescence glioblastoma (GBM) using next generation sequencing strategy.

Abstract

e14547 Background: Glioblastoma (GBM) is the most aggressive brain malignancy with a heterogeneity molecular profile and accounts for no more than 3-5% of Central Nervous System tumors in children. Despite its rarity, pediatric GBM pertain different molecular genetics, outcome and effectiveness to therapies and remains an equally lethal tumor in children. Identification of genetic alterations in GBM of childhood and adolescence is important to refine molecular classification, define prognosis and therapeutic strategies. We aimed to detect and investigate molecular changes with potential prognostic marker and therapeutic target in GBM, using next generation sequencing (NGS) strategy. Methods: We selected 41 GBM samples from patients treated at Pediatric Oncology Institute/GRAACC. NGS was performed to identified genetic alterations in tumor samples using Oncomine Childhood Cancer Research Assay (OCCRA) panel, specific genetic panel for childhood and adolescence neoplasms. Results: We selected 41 GBM samples and identified 33 mutated genes. The most commonly detected genetic alterations were involving TP53, PDGFRA, PIK3CA, NF1, MYC, MET and genes with histone-related functions, including H3F3A and ATRX. Mutations in H3F3A K28M, ATRX and TP53 were most recurrent. ATRX alterations, either nonsense substitution or frameshift deletion, were exclusively found in patients with H3F3A K28M mutations. TP53 loss-of-function was exclusive in 9 of 41 (22%) tumors. In 7 of 9 cases (78%) harboring both H3F3A and TP53 mutations, patients died due to disease progression . In these patients, H3F3A-TP53 mutation is suggested to be unfavorable prognostic factor. Copy number alterations were found in 30% of GBM cases and PDGFRA-amplifications were the most frequent. PDGFRA-amplification was exclusively found in patients with H3F3A K28M mutations and 75% of these patients did not survived longer than two years. Conclusions: Molecular profiling based on NGS genetic panel, specific for pediatric tumors, can provide information about potential prognostic biomarkers for GBM of childhood and adolescence. Thus, wider understanding about GBM biologic heterogeneity may lead to personalized therapeutic strategies for pediatric patients.