BACKGROUND: Fibroblast growth factor receptors (FGFRs) are frequently altered in cancers and present a potential therapeutic avenue. However, the type and prevalence of FGFR alterations in infiltrating gliomas (IGs) needs further investigation. OBJECTIVE: To understand the prevalence/type of FGFR alterations in IGs. METHODS: We reviewed clinicopathologic and genomic alterations of FGFR-mutant gliomas in a cohort of 387 patients. Tumors were examined by DNA next-generation sequencing for somatic mutations with a panel interrogating 205-genes. For comparison, cBioPortal databases were queried to identify FGFR-altered IGs. RESULTS: Fourteen patients (3.6%) with FGFR-mutant tumors were identified including 11 glioblastomas, Isocitrate hydrogenase (IDH) – wildtype (GBM-IDH-WT), 2 oligodendrogliomas, and 1 astrocytoma IDH-mutant. FGFR-altered IGs showed endocrinoid capillaries, microvascular proliferation, necrosis, oligodendroglioma-like cells, fibrin thrombi, microcalcifications, and nodular growth. FGFR3 was the most commonly altered FGFR gene (64.3%). The most common additional mutations in FGFR-altered IGs were TERTp, CDKN2A/B, PTEN, CDK4, MDM2, and TP53. FGFR3 alterations were only observed in GBM-IDH-WT. EGFR alterations were rarely identified in FGFR3-altered gliomas. CONCLUSIONS: Histologic features correlate with FGFR alterations in IGs. FGFR3-TACC3 fusion and FGFR3 amplification are the most common FGFR alterations in IGs. FGFR alterations are a rare, but potentially viable, therapeutic target in asubset of IGs.

Genomic alterations are critical for the diagnosis, prognostication, and treatment of patients with infiltrating gliomas. Telomerase reverse transcriptase promoter (TERTp) mutations are among such crucial alterations. Although DNA sequencing is the preferred method for identifying TERTp mutations, it has limitations related to cost and accessibility. We tested telomerase reverse transcriptase (TERT) immunohistochemistry (IHC) as a surrogate for TERTp mutations in infiltrating gliomas. Thirty-one infiltrating gliomas were assessed by IHC using an anti-TERT Y182 antibody. IHC results were analyzed by a board-certified neuropathologist. Tumors were analyzed by targeted nextgeneration sequencing. A literature review of the use of TERT antibodies as a surrogate for TERTp mutations was performed. Eighteen gliomas harbored TERTp mutations. Overall, TERT IHC demonstrated a sensitivity of 61.1% and a specificity of 69.2% for identifying TERTp mutations. Among the 19 IDH1/IDH2-wild-type gliomas, 16 (84%) harbored TERTp mutations, and TERT IHC had a sensitivity of 62.5% and a specificity of 33.3%. Among the 12 IDH1/IDH2-mutant gliomas, 2 (17%) harbored TERTp mutations, and TERT IHC had a sensitivity of 50% and a specificity of 80%. TERT IHC had low positive and negative likelihood values in the identification of TERTp mutations. The literature review included 5 studies with 645 patients and 4 different TERT antibodies. The results consistently showed poor sensitivity and specificity of TERT IHC for identifying TERTp mutations. TERT IHC is a suboptimal surrogate marker for TERTp mutations in infiltrating gliomas. The need remains for cost-effective, efficient, and accessible alternatives to next-generation sequencing for the evaluation of TERTp mutations in gliomas.