Clinico-pathological and epigenetic heterogeneity of diffuse gliomas with FGFR3::TACC3 fusion
Alice Métais, Arnault Tauziède‐Espariat, Jeremy Garcia, Romain Appay, Emmanuelle Uro‐Coste, David Meyronet, Claude‐Alain Maurage, Fanny Burel‐Vandenbos, Valérie Rigau, Dan Christian Chiforeanu, Johan Pallud, Sühan Senova, Raphaël Saffroy, Carole Colin, Myriam Edjlali, Pascale Varlet, Dominique Figarella-Branger, The Biopathology RENOCLIP-LOC network, Audrey Rousseau, Catherine Godfraind, Guillaume Gauchotte, Karima Mokhtari, Franck Bielle, Fabienne Escande, Fréderic Fina
Abstract
BACKGROUND: Gliomas with FGFR3::TACC3 fusion mainly occur in adults, display pathological features of glioblastomas (GB) and are usually classified as glioblastoma, IDH-wildtype. However, cases demonstrating pathological features of low-grade glioma (LGG) lead to difficulties in classification and clinical management. We report a series of 8 GB and 14 LGG with FGFR3:TACC3 fusion in order to better characterize them. METHODS: Centralized pathological examination, search for TERT promoter mutation and DNA-methylation profiling were performed in all cases. Search for prognostic factors was done by the Kaplan-Meir method. RESULTS: TERT promoter mutation was recorded in all GB and 6/14 LGG. Among the 7 cases with a methylation score > 0.9 in the classifier (v12.5), 2 were classified as glioblastoma, 4 as ganglioglioma (GG) and 1 as dysembryoplastic neuroepithelial tumor (DNET). t-SNE analysis showed that the 22 cases clustered into three groups: one included 12 cases close to glioblastoma, IDH-wildtype methylation class (MC), 5 cases each clustered with GG or DNET MC but none with PLNTY MC. Unsupervised clustering analysis revealed four groups, two of them being clearly distinct: 5 cases shared age (< 40), pathological features of LGG, lack of TERT promoter mutation, FGFR3(Exon 17)::TACC3(Exon 10) fusion type and LGG MC. In contrast, 4 cases shared age (> 40), pathological features of glioblastoma, and were TERT-mutated. Relevant factors associated with a better prognosis were age < 40 and lack of TERT promoter mutation. CONCLUSION: Among gliomas with FGFR3::TACC3 fusion, age, TERT promoter mutation, pathological features, DNA-methylation profiling and fusion subtype are of interest to determine patients' risk.