The molecular history of IDH-mutant astrocytomas without adjuvant treatment

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.

Keywords: CDKN2A; IDH‐mutant astrocytomas without adjuvant treatment; MYC.

FIGURE 1

Oncoprint summary of clinical and molecular profiles of 19 pairs of IDH‐mutant 1p19q non‐codeleted astrocytomas.

FIGURE 2

Percentage of copy number alterations in the genomes of matched primary tumors and recurrences.

FIGURE 3

Histological and FISH findings of primary and recurrent tumors of Patient 7, a 42‐year‐old female with an initial diagnosis of Grade 2 astrocytoma located at the frontal lobe. The patient received no temozolomide before all samples were collected. Top to bottom: Patient history timeline. H&E shows the histology at each tumor occurrence (all ×200). FISH confirmed the results of DNA methylation profiling. MYC was not amplified in the initial tumor. Upon the first, second and third recurrences, tumors acquired MYC gain. FISH also confirmed CDKN2A homozygous deletion at the third recurrence. CDKN2A was retained in the initial tumor and the first and second recurrences.

FIGURE 4

Histological and molecular features of primary and recurrent tumors of Patient 18, a 45‐year‐old male with an initial diagnosis of Grade 2 astrocytoma at the frontal lobe. This patient received no temozolomide treatment before all specimens were taken. Top to bottom: Patient history timeline. H&E staining illustrated the histology at each tumor occurrence (all ×200). FISH confirmed the results of DNA methylation profiling. The initial tumor showed no MYC gain, but at the first, second and third recurrences, the tumors acquired MYC gain. FISH also detected no CDKN2A homozygous deletion in the initial and first recurrent tumors. Upon the second and third recurrences, the tumors acquired CDKN2A homozygous deletion.

FIGURE 5

Phylogenetic trees of two IDH‐mutant, 1p19q non‐codeleted astrocytomas with multiple recurrences from Patients 7 and 18.