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

Matthew Wood, Tarik Tihan, Arie Perry, Geeta Chacko, Clinton Turner, Cunfeng Pu, Christopher Payne, Alexander Yu, Serguei I. Bannykh, David A. Solomon

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)192-202
Number of pages11
JournalBrain Pathology
Volume28
Issue number2
DOIs
StatePublished - Mar 1 2018
Externally publishedYes

Fingerprint

Neuroepithelial Neoplasms
Mutation
Fluorescence In Situ Hybridization
Neoplasm Genes
Glioma
Methylation
Genome
Neoplasms
DNA Fingerprinting
Gene Fusion
Trisomy
DNA Methylation
Glioblastoma
Blood Vessels
Histology
Pediatrics

Keywords

  • astroblastoma
  • CNS-HGNET-MN1
  • DNA methylation profiling
  • next-generation sequencing

ASJC Scopus subject areas

  • Neuroscience(all)
  • Pathology and Forensic Medicine
  • Clinical Neurology

Cite this

Multimodal molecular analysis of astroblastoma enables reclassification of most cases into more specific molecular entities. / Wood, Matthew; Tihan, Tarik; Perry, Arie; Chacko, Geeta; Turner, Clinton; Pu, Cunfeng; Payne, Christopher; Yu, Alexander; Bannykh, Serguei I.; Solomon, David A.

In: Brain Pathology, Vol. 28, No. 2, 01.03.2018, p. 192-202.

Research output: Contribution to journalArticle

Wood, M, Tihan, T, Perry, A, Chacko, G, Turner, C, Pu, C, Payne, C, Yu, A, Bannykh, SI & Solomon, DA 2018, 'Multimodal molecular analysis of astroblastoma enables reclassification of most cases into more specific molecular entities', Brain Pathology, vol. 28, no. 2, pp. 192-202. https://doi.org/10.1111/bpa.12561
Wood, Matthew ; Tihan, Tarik ; Perry, Arie ; Chacko, Geeta ; Turner, Clinton ; Pu, Cunfeng ; Payne, Christopher ; Yu, Alexander ; Bannykh, Serguei I. ; Solomon, David A. / Multimodal molecular analysis of astroblastoma enables reclassification of most cases into more specific molecular entities. In: Brain Pathology. 2018 ; Vol. 28, No. 2. pp. 192-202.
@article{b9a9e7ccc1b24c8e9f13eb4436e14cdc,
title = "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.",
keywords = "astroblastoma, CNS-HGNET-MN1, DNA methylation profiling, next-generation sequencing",
author = "Matthew Wood and Tarik Tihan and Arie Perry and Geeta Chacko and Clinton Turner and Cunfeng Pu and Christopher Payne and Alexander Yu and Bannykh, {Serguei I.} and Solomon, {David A.}",
year = "2018",
month = "3",
day = "1",
doi = "10.1111/bpa.12561",
language = "English (US)",
volume = "28",
pages = "192--202",
journal = "Brain Pathology",
issn = "1015-6305",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - Multimodal molecular analysis of astroblastoma enables reclassification of most cases into more specific molecular entities

AU - Wood, Matthew

AU - Tihan, Tarik

AU - Perry, Arie

AU - Chacko, Geeta

AU - Turner, Clinton

AU - Pu, Cunfeng

AU - Payne, Christopher

AU - Yu, Alexander

AU - Bannykh, Serguei I.

AU - Solomon, David A.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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.

AB - 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.

KW - astroblastoma

KW - CNS-HGNET-MN1

KW - DNA methylation profiling

KW - next-generation sequencing

UR - http://www.scopus.com/inward/record.url?scp=85045062726&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85045062726&partnerID=8YFLogxK

U2 - 10.1111/bpa.12561

DO - 10.1111/bpa.12561

M3 - Article

VL - 28

SP - 192

EP - 202

JO - Brain Pathology

JF - Brain Pathology

SN - 1015-6305

IS - 2

ER -