High-grade glioma with pleomorphic and pseudopapillary features (HPAP): a proposed type of circumscribed glioma in adults harboring frequent TP53 mutations and recurrent monosomy 13

Drew Pratt*, Zied Abdullaev, Antonios Papanicolau-Sengos, Courtney Ketchum, Pavalan Panneer Selvam, Hye Jung Chung, Ina Lee, Mark Raffeld, Mark R. Gilbert, Terri S. Armstrong, Peter Pytel, Ewa Borys, Joshua M. Klonoski, Matthew McCord, Craig Horbinski, Daniel Brat, Arie Perry, David Solomon, Charles Eberhart, Caterina GianniniMartha Quezado, Kenneth Aldape*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Tumors of the central nervous system (CNS) often display a wide morphologic spectrum that has, until recently, been the sole basis for tumor classification. The introduction of the integrated histomolecular diagnostic approach in CNS tumors has facilitated a classification system that is increasingly data-driven and with improved alignment to clinical outcome. Here, we report a previously uncharacterized glioma type (n = 31) using unsupervised clustering analysis of DNA methylation array data from approximately 14,000 CNS tumor samples. Histologic examination revealed circumscribed growth and morphologic similarities to pleomorphic xanthoastrocytoma (PXA), astroblastoma, ependymoma, polymorphous neuroepithelial tumor of the young (PLNTY), and IDH-wildtype glioblastoma (GBM). Median age (46.5 years) was significantly older than other circumscribed gliomas and younger than GBM. Dimensionality reduction with uniform manifold approximation and projection (UMAP) and hierarchical clustering confirmed a methylation signature distinct from known tumor types and methylation classes. DNA sequencing revealed recurrent mutations in TP53 (57%), RB1 (26%), NF1 (26%), and NF2 (14%). BRAF V600E mutations were detected in 3/27 sequenced cases (12%). Copy number analysis showed increased whole chromosome aneuploidy with recurrent loss of chromosome 13 (28/31 cases, 90%). CDKN2A/B deletion (2/31, 6%) and MGMT promoter methylation (1/31, 3%) were notably rare events. Most tumors showed features of a high-grade glioma, yet survival data showed significantly better overall survival compared to GBM (p < 0.0001). In summary, we describe a previously uncharacterized glioma of adults identified by a distinct DNA methylation signature and recurrent loss of chromosome 13.

Original languageEnglish (US)
Pages (from-to)403-414
Number of pages12
JournalActa Neuropathologica
Volume143
Issue number3
DOIs
StatePublished - Mar 2022

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Pathology and Forensic Medicine

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