ALTERNATIVE LENGTHENING OF TELOMERES (ALT) IS SEEN IN A PROPORTION OF OLIGODENDROGLIOMAS AND IT IS ASSOCIATED WITH A WORSE PROGNOSIS

Abstract

Abstract AIMS Oligodendrogliomas are well known to be mutated for TERTp, which is enigmatically a diagnostic criteria for molecular glioblastoma by WHO2021. It is generally believed that gliomas that are TERTp negative maintain their telomere lengths by means of Alternative Lengthening of Telomeres (ALT) which is usually reflected by mutations of ATRX. Oligodendrogliomas are known to be non-mutated for ATRX unlike astrocytomas. TERT re-arrangement has also been shown to be an alternative way of TERT activation. METHOD We evaluated 112 oligodendrogliomas of both Grades 2 (n=87) and 3 (n=25) (all IDH-mutant, 1p19q co-deleted and 93% TERTp mutated by Sanger sequencing) by FISH for ALT, MYC, PDGFRA, EGFR , CDKN2A HD, and +7/-10, the latter events being associated with malignant transformation in low-grade gliomas. RESULTS 40 cases (35.7%) showed ALT and ALT positivity was associated with worse PFS (p=.024) and remained an in- dependent prognosticator in multivariate analysis. Amplification was found in MYC (6.3%), PDGFRA (10.7%), EGFR (0.8%), CDKN2A HD (6.25%) and +7/-10 (0%) and they had no prognostic significance, likely due to low occurrences. ALT was found to be associated with MYC amplification (p=.004). ALT-positive cases were further evaluated by FISH for TERT re-arrangement, and targeted panel DNA sequencing. CIC mutation (62.1%) was as- sociated with shorter OS in Grade 2 tumours (p=.023) and was the only significant finding from panel sequencing. TERT re-arrangement was only seen in 10.7% and had no prognostic significance. CONCLUSIONS ALT is seen in a proportion of oligodendrogliomas in spite of TERTp mutations and is associated with a worse prognosis.