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

• Published in: Acta neuropathologica Vol. 145; no. 1; pp. 71 - 82
• Main Authors: Cimino, Patrick J., Ketchum, Courtney, Turakulov, Rust, Singh, Omkar, Abdullaev, Zied, Giannini, Caterina, Pytel, Peter, Lopez, Giselle Yvette, Colman, Howard, Nasrallah, MacLean P., Santi, Mariarita, Fernandes, Igor Lima, Nirschl, Jeff, Dahiya, Sonika, Neill, Stewart, Solomon, David, Perez, Eilis, Capper, David, Mani, Haresh, Caccamo, Dario, Ball, Matthew, Badruddoja, Michael, Chkheidze, Rati, Camelo-Piragua, Sandra, Fullmer, Joseph, Alexandrescu, Sanda, Yeaney, Gabrielle, Eberhart, Charles, Martinez-Lage, Maria, Chen, Jie, Zach, Leor, Kleinschmidt-DeMasters, B. K., Hefti, Marco, Lopes, Maria-Beatriz, Nuechterlein, Nicholas, Horbinski, Craig, Rodriguez, Fausto J., Quezado, Martha, Pratt, Drew, Aldape, Kenneth
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2023; Springer; Springer Nature B.V
• Subjects: Analysis; Astrocytoma; Astrocytoma - genetics; Astrocytoma - pathology; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Brain tumors; DNA methylation; DNA Methylation - genetics; Epigenetic inheritance; Epigenetics; Gene deletion; Gene fusion; Genetic disorders; Genomes; Genomics; Glioma; Gliomas; Homozygote; Humans; Kinases; MAP kinase; Medicine; Medicine & Public Health; Methylation; Mutation; Mutation - genetics; Neurofibromatosis; Neurofibromatosis 1 - genetics; Neurological disorders; Neuronal-glial interactions; Neurosciences; Next-generation sequencing; Original Paper; p53 Protein; Pathology; Phenotypes; Protein kinase; Recklinghausen's disease; RNA; RNA processing; Sequence Deletion; Tumor proteins; Tumors; NF1; DNA Methylation; Neurofibromatosis type 1; High-grade astrocytoma with piloid features; HGAP
• ISSN: 0001-6322; 1432-0533; 1432-0533
• DOI: 10.1007/s00401-022-02513-5

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.