PATH-20 - IDH mutant astrocytomas without receiving adjuvant treatment do not develop hypermutation or specific gene mutation and MYC, CDKN2A and PDGFRA are involved in malignant transformation

It is known that temozolomide treatment induces hypermutation and malignant transformation in IDH-mutant astrocytomas at recurrences and “wait-and-see” after resection is acceptable post-operative management. Although a small number of adjuvant-treatment-naive IDH-mutant low-grade astrocytomas have been embedded in well known series of longitudinal gliomas, little specific information is available about the natural evolution of IDH-mutant astrocytoma without selection pressures of temozolomide and irradiation. We studied 19 patients for tissues from primary and recurrent IDH-mutant 1p19q non-deleted Grade 2 gliomas and where no alkylating therapy or radiation was given between primary tumors and malignantly transformed recurrences (2 patients with multiple recurrences). Mean and median follow-ups were 123.1 and 138.8 months. We performed FISH for amplifications for MYC, PDGFRA, homozygous deletion (HD) for CDKN2A and for Alternative Lengthening for Telomeres (ALT). In the paired tumors from 12 patients, panel sequencing was performed. ATRX, p53, IDH mutations and ALT co-occurred in both primary and recurrent tumors for the same patients. MYC was found in tumors from 5/19 patients, three of which were found in the recurrences but not primary tumors. PDGFRA amplification was seen in tumors from six patients, four only in recurrences. Tumors from 11/19 patients showed either CDKN2A HD, MYC or PDGFRA amplification at recurrences. No hypermutated tumors could be found. Only 131 of a total 255 mutations were acquired in the recurrences. NOTCH1 mutation was found only in tumors from 2 patients. No recurrence-specific mutation was identified. p53 mutations when occurring in the primary tumors were associated with a shorter PFS (p=0.011). No mutation of the mismatch repair genes was found and only one POLE mutation was found.

Conclusion: IDH-mutant low grade astrocytomas not being treated with temozolomide or irradiation do not develop hypermutation or specific gene mutation for their natural evolution and malignant transformation.