Expanded analysis of high-grade astrocytoma with piloid features identifies an epigenetically and clinically distinct subtype associated with neurofibromatosis type 1.

Journal Article (Journal Article)

High-grade astrocytoma with piloid features (HGAP) is a recently recognized glioma type whose classification is dependent on its global epigenetic signature. HGAP is characterized by alterations in the mitogen-activated protein kinase (MAPK) pathway, often co-occurring with CDKN2A/B homozygous deletion and/or ATRX mutation. Experience with HGAP is limited and to better understand this tumor type, we evaluated an expanded cohort of patients (n = 144) with these tumors, as defined by DNA methylation array testing, with a subset additionally evaluated by next-generation sequencing (NGS). Among evaluable cases, we confirmed the high prevalence CDKN2A/B homozygous deletion, and/or ATRX mutations/loss in this tumor type, along with a subset showing NF1 alterations. Five of 93 (5.4%) cases sequenced harbored TP53 mutations and RNA fusion analysis identified a single tumor containing an NTRK2 gene fusion, neither of which have been previously reported in HGAP. Clustering analysis revealed the presence of three distinct HGAP subtypes (or groups = g) based on whole-genome DNA methylation patterns, which we provisionally designated as gNF1 (n = 18), g1 (n = 72), and g2 (n = 54) (median ages 43.5 years, 47 years, and 32 years, respectively). Subtype gNF1 is notable for enrichment with patients with Neurofibromatosis Type 1 (33.3%, p = 0.0008), confinement to the posterior fossa, hypermethylation in the NF1 enhancer region, a trend towards decreased progression-free survival (p = 0.0579), RNA processing pathway dysregulation, and elevated non-neoplastic glia and neuron cell content (p < 0.0001 and p < 0.0001, respectively). Overall, our expanded cohort broadens the genetic, epigenetic, and clinical phenotype of HGAP and provides evidence for distinct epigenetic subtypes in this tumor type.

Full Text

Duke Authors

Cited Authors

  • Cimino, PJ; Ketchum, C; Turakulov, R; Singh, O; Abdullaev, Z; Giannini, C; Pytel, P; Lopez, GY; Colman, H; Nasrallah, MP; Santi, M; Fernandes, IL; Nirschl, J; Dahiya, S; Neill, S; Solomon, D; Perez, E; Capper, D; Mani, H; Caccamo, D; Ball, M; Badruddoja, M; Chkheidze, R; Camelo-Piragua, S; Fullmer, J; Alexandrescu, S; Yeaney, G; Eberhart, C; Martinez-Lage, M; Chen, J; Zach, L; Kleinschmidt-DeMasters, BK; Hefti, M; Lopes, M-B; Nuechterlein, N; Horbinski, C; Rodriguez, FJ; Quezado, M; Pratt, D; Aldape, K

Published Date

  • January 2023

Published In

Volume / Issue

  • 145 / 1

Start / End Page

  • 71 - 82

PubMed ID

  • 36271929

Pubmed Central ID

  • PMC9844520

Electronic International Standard Serial Number (EISSN)

  • 1432-0533

International Standard Serial Number (ISSN)

  • 0001-6322

Digital Object Identifier (DOI)

  • 10.1007/s00401-022-02513-5


  • eng