Recent data have led to a re-classification of pHGGs based on molecular subgrouping. In adult gliomas, IDH1 and TERTp mutations represent key molecular alterations, whereas in pHGGs are rare. A significant difference between pediatric and adult gliomas is the frequency of histone H3F3A mutations, frequently reported in pHGGs, while are nearly absent in adults. The most common variants affect amino acid 34 and 27 (G34R/V and K27M), representing different clinico-pathological and biological subgroups. Elongation of telomeres, necessary for tumor cell immortalization, can be performed via reactivation of telomerase or ALT. TERTp mutations and hyper-methylation result in up-regulation of telomerase activity; neoplastic cells, which do not reactivate telomerase, trigger ALT. Previous studies have identified a connection of ATRX and H3F3A mutations with ALT phenotype in gliomas. However, an extensive evaluation of the association of telomeres elongation with specific molecular subgroups of pHGG is still lacking, the comparison between pHGG K27M and G34R/V mutated, in terms of ALT activation, was not elucidated.
The aim of the project is to investigate which genetic alterations trigger ALT in different molecular subgroups of pHGG, in order to evidence the involvement of each genetic alteration in tumor cell senescence escape by telomeres elongation, defining the differences of each molecular subgroup and extending the knowledge on the biology of the H3.3-mutated (G34, K27) pHGGs. We will screen a cohort of histological revised pHGGs using Telo-FISH to evaluate telomeres length; loss of ATRX expression will be analyzed by IHC, H3F3A and TERTp mutations by sequencing, TERTp methylation by MS-PCR. Finally, data will be correlated to patients survival using Kaplan-Meier method. With this project we hope to translate our results into patient benefit, contributing to the risk stratification definition, and to application of new targeted treatments for a subset of these tumors.
