Multimodal molecular analysis of astroblastoma enables reclassification of most cases into more specific molecular entities

Abstract

Astroblastoma is a rare and controversial glioma with variable clinical behavior. The diagnosis currently rests on histologic findings of a circumscribed glioma with astroblastomatous pseudorosettes and vascular hyalinization. Immunohistochemical studies have suggested different oncogenic drivers, such as BRAF p.V600E, but very few cases have been studied using genome-wide methodologies. Recent genomic profiling identified a subset of CNS embryonal tumors with astroblastoma-like morphology that harbored MN1 gene fusions, termed "CNS high-grade neuroepithelial tumors with MN1 alteration" (CNS-HGNET-MN1). To further characterize the genetic alterations that drive astroblastomas, we performed targeted next-generation sequencing (NGS) of 500 cancer-associated genes in a series of eight cases. We correlated these findings with break-apart fluorescence in situ hybridization (FISH) analysis of the MN1 locus and genome-wide DNA methylation profiling. Four cases showed MN1 alteration by FISH, including two pediatric cases that lacked other pathogenic alterations, and two adult cases that harbored other cancer-associated gene mutations or copy number alterations (eg, CDKN2A/B homozygous deletion, TP53, ATM and TERT promoter mutations). Three of these cases grouped with the CNS-HGNET-MN1 entity by methylation profiling. Two of four MN1 intact cases by FISH showed genetic features of either anaplastic pleomorphic xanthoastrocytoma (BRAF p.V600E mutation, CDKN2A/B homozygous deletion and TERT promoter mutation) or IDH-wildtype glioblastoma (trisomy 7, monosomy 10, CDK4 amplification and TP53, NRAS and TERT promoter mutations) and these cases had an aggressive clinical course. Two clinically indolent cases remained unclassifiable despite multimodal molecular analysis. We conclude that astroblastoma histology is not specific for any entity including CNS-HGNET-MN1, and that additional genetic characterization should be considered for astroblastomas, as a number of these tumors likely contain a methylation profile or genetic alterations that suggest classification as other tumor entities. Our heterogeneous molecular findings help to explain the clinical unpredictability of astroblastoma.

Astroblastoma: a distinct tumor entity characterized by alterations of the X chromosome and MN1 rearrangement

“…More recently, Wood et al . also reported MN1 alteration in four of eight CNS tumors that exhibited astroblastoma‐like morphology .…”

BRAF V600E‐mutated central nervous system tumor with divergent morphological feature – Anaplastic pleomorphic xanthoastrocytoma‐like and astroblastoma‐like

“…This particular case was a biopsy specimen and initially diagnosed as anaplastic astroblastoma. The patient had a rapid recurrence and died after 2 years . Similarly, the present case was BRAF V600E‐mutated and in addition to astroblastic areas also showed morphological areas corresponding to PXA‐A.…”

Targeted fusion analysis can aid in the classification and treatment of pediatric glioma, ependymoma, and glioneuronal tumors

“…These fusions were observed in a subset of tumors previously defined as PNET. Although many MN1 ‐fused tumors showed a nonspecific primitive neuroectodermal (PNET‐like) morphology, a subset had classic features of astroblastoma, an entity previously histologically characterized by the presence of perivascular pseudorosettes composed of tumor cells with thick broad processes extending to a central blood vessel, often with hyalinized walls . These findings led to the review of molecular findings in histologically defined astroblastomas, a large proportion of which were shown to have MN1 alterations.…”

“…These findings led to the review of molecular findings in histologically defined astroblastomas, a large proportion of which were shown to have MN1 alterations. The current understanding is that although astroblastoma histology is not specific to any particular tumor entity, a large number show MN1 alterations and cluster best with CNS high‐grade neuroepithelial tumors . A recent study of MN1‐altered tumors with astroblastoma histology showed good prognosis unlike that expected for PNET.…”