Clinico-pathological and epigenetic heterogeneity of diffuse gliomas with FGFR3::TACC3 fusion

authors

• Métais Alice
• Tauziède-Espariat Arnault
• Garcia Jeremy
• Appay Romain
• Uro-Coste Emmanuelle
• Meyronet David
• Maurage Claude Alain
• Vandenbos Fanny Burel
• Rigau Valérie
• Chiforeanu Dan Christian
• Pallud Johan
• Senova Suhan
• Saffroy Raphaël
• Colin Carole
• Edjlali Myriam
• Varlet Pascale
• Figarella-Branger Dominique F.

keywords

• 2021 WHO classification of CNS tumours
• DNA-methylation profiling
• FGFR3TACC3 fusion
• Glioblastoma
• Pediatric low grade glioma

document type

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.

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