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

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.

FGFR families: biological functions and therapeutic interventions in tumors

“…264 Similarly, a newly identified splicing mutant, FGFR3Δ7-9, which directly connects exon 6 and exon 10, directly phosphorylates the ten-eleven translocation-2 DNA demethylase and causes its ubiquitinated degradation, activating the AKT pathway to promote the proliferation of HCC. 125,265 FGFR3 may also undergo rearrangements or amplifications in gliomas 266,267 and lung cancer. 268,269 In glioma, the most common fusion partner of FGFR3 is TACC3, and the fusion process of FGFR3-TACC3, which requires HSP90, requires the involvement of cell division cycle 37 (CDC37).…”

“…FGFR3 may also undergo rearrangements or amplifications in gliomas 266,267 and lung cancer 268,269 . In glioma, the most common fusion partner of FGFR3 is TACC3, and the fusion process of FGFR3–TACC3, which requires HSP90, requires the involvement of cell division cycle 37 (CDC37) 270 .…”

A diffuse glioma with oligodendroglial‐like cells and extensive calcifications

“…Diffuse gliomas with FGFR3:TACC3 fusion do not represent a distinct nosological entity in the 2021 WHO classification of CNS tumors. Most reported cases had a high‐grade morphology, consisting of microvascular proliferation and necrosis [ 1 , 2 ] and were considered to represent a subgroup of IDH wild‐type GBMs distinguished by prolonged overall survival. Within the minor proportion of diffuse gliomas with FGFR3::TACC3 fusion that lack histological signs of malignancy, some cases are also devoid of the molecular features of GBMs, whereas others have chromosomes 7 gain/10 loss and/or pTERT mutation [ 1 , 2 ], which supports a diagnosis of GBM, IDH ‐wildtype, according to the 2021 WHO CNS classification, as in the present case.…”

“…It has been suggested that these tumors may represent precursors of GBM or undersampled GBMs. Two studies have shown that the majority exhibit a distinct DNA methylation profile [ 1 , 2 ]. Indeed, of 27 histologically diffuse low‐grade gliomas with FGFR3::TACC3 fusion and pTERT mutation and/or chromosomes 7 gain/10 loss, only five cases had a calibration score above 0.90 for the methylation class “GBM IDH‐wildtype” using the 11b4 version of the Heidelberg classifier [ 1 , 2 ].…”

“…Two studies have shown that the majority exhibit a distinct DNA methylation profile [ 1 , 2 ]. Indeed, of 27 histologically diffuse low‐grade gliomas with FGFR3::TACC3 fusion and pTERT mutation and/or chromosomes 7 gain/10 loss, only five cases had a calibration score above 0.90 for the methylation class “GBM IDH‐wildtype” using the 11b4 version of the Heidelberg classifier [ 1 , 2 ]. Using the 12.5 version of the classifier, two tumors had calibration scores of 0.98 and 0.99 for the methylation class “ganglioglioma,” and none of the remaining cases had a calibrated score above 0.90 for any methylation classes [ 1 , 2 ].…”