title: Genomic characterization of recurrent high-grade astroblastoma.
abstract: Astroblastomas are rare primary brain tumors, diagnosed based on histologic features. Not currently assigned a WHO grade, they typically display indolent behavior, with occasional variants taking a more aggressive course. We characterized the immunohistochemical characteristics, copy number (high-resolution array comparative genomic hybridization, OncoCopy) and mutational profile (targeted next-generation exome sequencing, OncoPanel) of a cohort of seven biopsies from four patients to identify recurrent genomic events that may help distinguish astroblastomas from other more common high-grade gliomas. We found that tumor histology was variable across patients and between primary and recurrent tumor samples. No common molecular features were identified among the four tumors. Mutations commonly observed in astrocytic tumors (IDH1/2, TP53, ATRX, and PTEN) or ependymoma were not identified. However one case with rapid clinical progression displayed mutations more commonly associated with GBM (NF1(N1054H/K63)*, PIK3CA(R38H) and ERG(A403T)). Conversely, another case, originally classified as glioblastoma with nine-year survival before recurrence, lacked a GBM mutational profile. Other mutations frequently seen in lower grade gliomas (BCOR, BCORL1, ERBB3, MYB, ATM) were also present in several tumors. Copy number changes were variable across tumors. Our findings indicate that astroblastomas have variable growth patterns and morphologic features, posing significant challenges to accurate classification in the absence of diagnostically specific copy number alterations and molecular features. Their histopathologic overlap with glioblastoma will likely confound the observation of long-term GBM "survivors". Further genomic profiling is needed to determine whether these tumors represent a distinct entity and to guide management strategies.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Tejus A
authors.initials: TA
authors.lastname: Bale
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, USA; Department of Pathology, King Fahad Medical City, Riyadh, Saudi Arabia.
authors.forename: Malak
authors.initials: M
authors.lastname: Abedalthagafi
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Wenya Linda
authors.initials: WL
authors.lastname: Bi
authors.affiliation: Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Yun Jee
authors.initials: YJ
authors.lastname: Kang
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Parker
authors.initials: P
authors.lastname: Merrill
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Dunn
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Dubuc
authors.affiliation: Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Charbonneau
authors.affiliation: Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Loreal
authors.initials: L
authors.lastname: Brown
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Azra H
authors.initials: AH
authors.lastname: Ligon
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Shakti H
authors.initials: SH
authors.lastname: Ramkissoon
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, USA. Electronic address: keith_ligon@dfci.harvard.edu.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D005260:Female; D018628:Gene Dosage; D055106:Genome-Wide Association Study / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D018302:Neoplasms, Neuroepithelial / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA
keywords: Astroblastoma; GBM; NGS; SETD2; aCGH