Alternative Lengthening of Telomeres (ALT) mechanism in Pediatric High Grade Gliomas

Proponente Francesca Romana Buttarelli - Professore Associato
Sottosettore ERC del proponente del progetto
Componenti gruppo di ricerca
Componente Categoria
Konstantinos Giannakakis Componenti strutturati del gruppo di ricerca
Felice Giangaspero Componenti strutturati del gruppo di ricerca
Francesca Gianno Dottorando/Assegnista/Specializzando componente non strutturato del gruppo di ricerca
Componente Qualifica Struttura Categoria
Maura Massimino Oncologo Direttore Oncologia Pediatrica, Fondazione IRCCS Istituto Nazionale Tumori, Milano Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca
Manuela Badiali Biologo Responsabile Laboratorio Centro Trapianti midollo osseo, Ospedale Microcitemico Cagliari Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca
Torsten Pietsch Neuropatologo Professor and Chairman Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn, Germany Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca
Simone Minasi Biotecnologo Biotecnologo, contratto collaborazione Fondazione Neuroblastoma, presso Sapienza Università di Roma Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca

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 H3F3A mutations; histone mutations are frequently reported in pHGGs, while are nearly absent in adults. The most common variants affect two amino acid on H3.3 (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 each specific molecular subgroup of pHGG is still lacking; in particular, 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 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 pHGGs. We will screen a cohort of histological revised pHGGs using Telomer-specific 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 and application of new targeted treatments for a subset of these tumors.

LS2_1, LS1_10, LS2_5

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