Pilocytic Astrocytoma (PAST)

Overview

Pilocytic Astrocytoma is a low-grade CNS/Brain tumor classified under Encapsulated Glioma (ENCG) in the OncoTree hierarchy (tissue: CNS/Brain, mainType: Glioma, OncoTree level 3). It is among the most genomically homogeneous solid tumors, characterized by near-universal activation of the MAPK pathway — most commonly via the KIAA1549::BRAF fusion. Pilocytic astrocytoma occurs predominantly in children and young adults and carries a generally favorable prognosis relative to higher-grade gliomas.

Cohorts in the corpus

  • MSK-IMPACT / MSK-ACCESS / MSK-Fusion cohort (97,024 samples, 69,337 patients, January 2014 – November 2022): 29 pilocytic astrocytoma cases harboring oncogenic BRAF fusions detected (56% de novo BRAF fusion prevalence, highest of all 52 histologies profiled). Data deposited as braf_msk_archer_2024 and braf_msk_impact_2024. PMID:38922339

Recurrent alterations

  • KIAA1549::BRAF fusion: present in 90% of pilocytic astrocytoma BRAF fusion cases (N=29); constitutes the dominant oncogenic driver. PMID:38922339
  • BRAF fusions (all partners): de novo prevalence 56% in pilocytic astrocytoma, the highest prevalence across 52 histologies in a tumor-agnostic MSK cohort. BRAF fusions activate the MAPK pathway via constitutive kinase dimerization (class II mechanism). PMID:38922339
  • BRAF fusions are mutually exclusive with other MAPK pathway alterations in this cohort. PMID:38922339
  • WGS of 96 pilocytic astrocytomas (ICGC PedBrain) confirmed 100% MAPK pathway alteration (lowest mutation rate of any solid tumor, <0.1/Mb); identified FGFR1 kinase-domain hotspot mutations (N546, K656) in non-cerebellar tumors, novel NTRK2 fusions (QKI:NTRK2, NACC2:NTRK2), and four new BRAF fusion partners PMID:23817572
  • Used as a molecular comparator in the TCGA pan-glioma study; 61 grade-I PAs all clustered with the PA-like methylation subtype (LGm6), which constitutes a favorable-prognosis IDH-wildtype subset with MAPK-pathway alterations in 52% of cases and largely euploid copy-number profiles PMID:26824661

Subtypes

No molecular subtypes of pilocytic astrocytoma were distinguished in the corpus beyond fusion partner identity. Histology-level distinction from other low-grade CNS tumors (ganglioglioma, low-grade neuroepithelial tumor) was noted but not further subclassified in the available papers.

Therapeutic landscape

  • MEK inhibitors (trametinib, selumetinib): All 6 evaluable pilocytic astrocytoma patients treated with MEK inhibitor monotherapy remained on therapy >6 months (median 11 months, range 6–26 months), representing the most durable responses observed among BRAF fusion-positive tumor types in this cohort. PMID:38922339
  • BRAF + MEK inhibitor combination: less durable than MEK inhibitor monotherapy in this tumor type (median 1 month across all histologies); combination benefit in pilocytic astrocytoma specifically was not separately reported. PMID:38922339
  • Emerging approaches include BRAF dimer blockers, ERK inhibitors, and PROTACs targeting BRAF fusions. PMID:38922339

Sources

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