Abstract

Hypermutation and malignant transformation are potential complications arising from temozolomide treatment of IDH-mutant gliomas. However, the natural history of IDH-mutant low-grade gliomas without temozolomide treatment is actually under-studied. We retrieved retrospectively from our hospitals paired tumors from 19 patients with IDH-mutant, 1p19q non-codeleted Grade 2 astrocytomas where no interim adjuvant treatment with either temozolomide or radiotherapy was given between primary resections and first recurrences. Tissues from multiple recurrences were available from two patients and radiotherapy but not temozolomide was given before the last specimens were resected. We studied the natural molecular history of these low-grade IDH-mutant astrocytomas without pressure of temozolomide with DNA methylation profiling and copy number variation (CNV) analyses, targeted DNA sequencing, TERTp sequencing, FISH for ALT and selected biomarkers. Recurrences were mostly higher grades (15/19 patients) and characterized by new CNVs not present in the primary tumors (17/19 cases). Few novel mutations were identified in recurrences. Tumors from 17/19 (89.5%) patients showed either CDKN2A homozygous deletion, MYC or PDGFRA focal and non-focal gains at recurrences. There was no case of hypermutation. Phylogenetic trees constructed for tumors for the two patients with multiple recurrences suggested a lack of subclone development in their evolution when under no pressure from temozolomide. In summary, our studies demonstrated, in contrast to the phenomenon of temozolomide-induced hypermutation, IDH-mutant, 1p19q non-codeleted Grade 2 astrocytomas which had not been treated by temozolomide, acquired new CNVs at tumor recurrences. These findings improve our understanding of the molecular life history of IDH-mutant astrocytomas.