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==Links== | ==Links== | ||
[https://www.cancer.gov/rare-brain-spine-tumor/tumors/pleomorphic-xanthroastrocytoma Pleomorphic Xanthoastrocytoma (PXA) and Other BRAF-Altered Tumors: Diagnosis and Treatment - NCI] | [https://www.cancer.gov/rare-brain-spine-tumor/tumors/pleomorphic-xanthroastrocytoma Pleomorphic Xanthoastrocytoma (PXA) and Other BRAF-Altered Tumors: Diagnosis and Treatment - NCI] | ||
==References==<references /> | ==References== | ||
<references /> | |||
==Notes== | ==Notes== | ||
Latest revision as of 19:51, 25 February 2026
Central Nervous System Tumours (WHO Classification, 5th ed.)
(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page).
Primary Author(s)*
Wahab A. Khan, PhD, FACMG, Dartmouth Health
WHO Classification of Disease
| Structure | Disease |
|---|---|
| Book | Central Nervous System Tumours (5th ed.) |
| Category | Gliomas, glioneuronal tumours, and neuronal tumours |
| Family | Gliomas, glioneuronal tumours, and neuronal tumours |
| Type | Circumscribed astrocytic gliomas |
| Subtype(s) | Pleomorphic xanthoastrocytoma |
Related Terminology - Pleomorphic xanthoastrocytoma (PXA)
| Acceptable | N/A |
| Not Recommended | Pleomorphic xanthoastrocytoma with anaplastic features; anaplastic pleomorphic xanthoastrocytoma (for CNS WHO grade 3) |
Gene Rearrangements
| Driver Gene | Fusion(s) and Common Partner Genes | Molecular Pathogenesis | Typical Chromosomal Alteration(s) | Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease) | Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|---|
| BRAF | BRAF-KIAA1549 (rare), RAF1 fusions, NTRK2/ALK/NTRK1 (very rare in PXA) | Aberrant MAPK pathway activation (i.e BRAF p.V600E variant) | N/A | BRAF p.V600E: Common in PXA, Fusions: Rare | D, P, T | Yes (WHO 2021/2025, NCCN 2023)[1] | BRAF p.V600E is diagnostic and predictive; kinase fusions targetable in rare cases[2][3] [4][5] |
| CDKN2A/B | N/A | Loss leads to cell cycle dysregulation | CDKN2A/B homozygous deletion (9p21); chr7 gain; chr10/22 loss | Common | D, P | Yes (WHO, NCCN—context specific) | Co-occurrence with BRAF p.V600E supports PXA diagnosis |
| TERT | N/A | Telomerase activation (mainly in anaplastic PXA) | TERT promoter mutations/amplifications | Recurrent (15–47% in anaplastic)[6] | P (poor; recurrence risk) | Yes (WHO, NCCN-context specefic) | Seen mainly in grade 3/anaplastic; adverse outcome[2]
|
| NTRK2, ALK, RAF1 | Fusions: NACC2-NTRK2, BEND5-NTRK2, PPP1CB-ALK, etc. | MAPK pathway activation via kinase fusions | Variable; not associated with classic chr alterations | Rare (<5%)[7] | D | Context-dependent ( e.g. For patients with CNS tumors who harbor NTRK fusions, TRK inhibitors such as larotrectinib or repotrectinib are considered a preferred therapy, regardless of histology, if other options are limited) NCCN CNS Cancer guidelines | Reported in individual cases; more common in glioneuronal/low-grade gliomas |
Individual Region Genomic Gain/Loss/LOH
| Chr # | Gain, Loss, Amp, LOH | Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] | Relevant Gene(s) | Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| 9p21 | Homozygous loss, LOH | 9p21.3; chr9:21,900,000-22,300,000 (GRCh38; ~400Kb) | CDKN2A, CDKN2B | D, P | Yes (WHO CNS5, NCCN) | Defining PXA feature; occurs in >85% of cases[8] |
| 7 | Gain | Chr7 whole arm or segmental (varies) | EGFR not typically amplified) | D | No (however, frequently mentioned in literature as a recurrent copy number change in PXA[9] | Trisomy, supports diagnosis; also seen in other gliomas |
| 22 | Loss | Whole chr22 (varied cytoband, arm) | NF2, others | D | No (not guideline-specific, recurrent in PXA) | Frequently reported, may occur with other losses |
| 8p | Loss | chr 8p (varied region) | Varies | P | No | Seen in a subset, less common |
| LOH | Copy-neutral | Varies (mainly 9p21) | CDKN2A, CDKN2B | D, P | Yes (NCCN) | copy-neutral LOH; supports diagnosis |
Characteristic Chromosomal or Other Global Mutational Patterns
| Chromosomal Pattern | Molecular Pathogenesis | Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|
| Common chromosome gains: +7, +5, +2, +12, +20, +21, +15 | Variable; chromosomal hyperdiploidy | Recurrent (17-20%) | P | No | Whole chromosome gains common; gains of +12 and +21 more common in BRAF V600E tumors; may indicate genomic instability[8] |
| Whole chromosome loss or cnLOH most commonly involved chromosomes 22, 14, 13, and 10 | Variable gene losses | Recurrent | P | No | Seen in subset; trend toward anaplastic cases[8] |
| Complex karyotype with multiple CNVs | Chromosomal instability (CIN) | Common | P | No | Includes polyploidy, subclones, mosaicism; complexity increases at recurrence/progression[8] |
| Pleomorphic xanthoastrocytoma (PXA) not identified as a high‑TMB or focal amplifications. No MSI‑driven marker in PXA. Global mutation pattern in PXA dominated by MAPK activation (BRAF or kinase fusions) plus CDKN2A/B loss | CDKN2A/B loss and loss of p16/p14ARF tumor suppressors; cell cycle dysregulation | Common | P,D | Yes | CDKN2A/B loss defining feature of PXA; not associated with grade or BRAF status; central to PXA biology |
Gene Mutations (SNV/INDEL)
This table is not meant to be an exhaustive list
| Gene | Genetic Alteration | Tumor Suppressor Gene, Oncogene, Other | Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| BRAF
|
p.V600E missense activating mutation | Oncogene | Common (~60–80%) | D, P, T | Yes (WHO CNS5, NCCN) | Specific for PXA, actionable with BRAF/MEK inhibitors; rarely found in diffuse astrocytomas. Favorable prognostic marker[10] |
| TERT
|
Promoter mutation | Other | Recurrent | P | Yes (WHO CNS5) | Associated with anaplastic progression, poor recurrence-free survival, and adverse prognosis in high-grade PXA[10] |
| IDH1/IDH2 | Missense (R132H, etc) | Other | Absent in classic PXA | D | Yes (WHO CNS5 for differential diagnosis) | Absence confirms classic PXA; if present, suggests diffuse astrocytoma not PXA[11] |
| NTRK2, ALK | Kinase gene fusions | Oncogene | Rare | T | Yes (FDA/NCCN for fusion-positive CNS tumors, not PXA-specific) | Targetable by TRK/ALK inhibitors (larotrectinib, entrectinib); found chiefly in pediatric BRAF-wildtype PXAs[12] |
Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
Epigenomic Alterations
Dominant epigenomic themes in Pleomorphic xanthoastrocytoma (PXA) are: a distinct methylation class tied to MAPK activation and CDKN2A/B loss, progressive promoter hypermethylation in anaplastic transformation, frequent MGMT promoter methylation, and a relative absence of the H3/ATRX-driven epigenetic programs seen in other glioma subtypes[13][14].
Genes and Main Pathways Involved
| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| BRAF and MAP2K1; Activating mutations | MAPK signaling | Increased cell growth and proliferation |
| CDKN2A; Inactivating mutations | Cell cycle regulation | Unregulated cell division |
| TERT promoter mutations or amplification | TERT – Telomere maintenance pathway | Activate telomerase and support immortalization via the telomere maintenance pathway |
Genetic Diagnostic Testing Methods
Diagnostic workup for suspected PXA typically includes BRAF mutation testing, robust assessment of CDKN2A/B deletion (preferably via SNP-microarray or NGS/ddPCR), and DNA methylation profiling, with extended NGS/fusion testing where needed[15]
Familial Forms
For most PXAs, no inherited/familial cause is identified, and they are considered sporadic tumors.
Additional Information
PXA belongs to a specific DNA methylation class characterized by BRAF pathway activation (usually BRAF p.V600E) and near‑universal CDKN2A/B homozygous deletion, and is typically IDH1/2‑ and H3‑wildtype; methylation profiling is increasingly used to confirm this integrated molecular diagnosis and to distinguish PXA from pilocytic astrocytoma and epithelioid glioblastoma[16].
Links
Pleomorphic Xanthoastrocytoma (PXA) and Other BRAF-Altered Tumors: Diagnosis and Treatment - NCI
References
- ↑ d’Amati, Antonio; et al. (2024-03-13). "Pediatric CNS tumors and 2021 WHO classification: what do oncologists need from pathologists?". Frontiers in Molecular Neuroscience. 17. doi:10.3389/fnmol.2024.1268038. ISSN 1662-5099.
- ↑ 2.0 2.1 Phillips, Joanna J.; et al. (2019-01). "The genetic landscape of anaplastic pleomorphic xanthoastrocytoma". Brain Pathology (Zurich, Switzerland). 29 (1): 85–96. doi:10.1111/bpa.12639. ISSN 1750-3639. PMC 7837273 Check
|pmc=value (help). PMID 30051528. Check date values in:|date=(help) - ↑ Vaubel, Rachael A.; et al. (2018-03). "Recurrent copy number alterations in low-grade and anaplastic pleomorphic xanthoastrocytoma with and without BRAF V600E mutation". Brain Pathology (Zurich, Switzerland). 28 (2): 172–182. doi:10.1111/bpa.12495. ISSN 1750-3639. PMC 5807227. PMID 28181325. Check date values in:
|date=(help) - ↑ Tian, Lei; et al. (2025). "Pleomorphic xanthoastrocytoma with multiple recurrences and continuous malignant progression to bone metastasis: a case report". Frontiers in Surgery. 12: 1595199. doi:10.3389/fsurg.2025.1595199. ISSN 2296-875X. PMC 12174448 Check
|pmc=value (help). PMID 40535548 Check|pmid=value (help). - ↑ Di Nunno, Vincenzo; et al. (2022). "Implications of BRAF V600E mutation in gliomas: Molecular considerations, prognostic value and treatment evolution". Frontiers in Oncology. 12: 1067252. doi:10.3389/fonc.2022.1067252. ISSN 2234-943X. PMC 9846085 Check
|pmc=value (help). PMID 36686797 Check|pmid=value (help). - ↑ Phillips, Joanna J.; et al. (2019-01). "The genetic landscape of anaplastic pleomorphic xanthoastrocytoma". Brain Pathology (Zurich, Switzerland). 29 (1): 85–96. doi:10.1111/bpa.12639. ISSN 1750-3639. PMC 7837273 Check
|pmc=value (help). PMID 30051528. Check date values in:|date=(help) - ↑ Galbraith, Kristyn; et al. (2024-01-02). "Impact of Rare and Multiple Concurrent Gene Fusions on Diagnostic DNA Methylation Classifier in Brain Tumors". Molecular cancer research: MCR. 22 (1): 21–28. doi:10.1158/1541-7786.MCR-23-0627. ISSN 1557-3125. PMC 10942665 Check
|pmc=value (help). PMID 37870438 Check|pmid=value (help). - ↑ 8.0 8.1 8.2 8.3 Vaubel RA, Caron AA, Yamada S, Decker PA, Eckel Passow JE, Rodriguez FJ, Nageswara Rao AA, Lachance D, Parney I, Jenkins R, Giannini C. Recurrent copy number alterations in low-grade and anaplastic pleomorphic xanthoastrocytoma with and without BRAF V600E mutation. Brain Pathol. 2018 Mar;28(2):172-182. doi: 10.1111/bpa.12495. Epub 2017 Apr 2. PMID: 28181325; PMCID: PMC5807227.
- ↑ Vaubel, Rachael; et al. (2021-01). "Biology and grading of pleomorphic xanthoastrocytoma-what have we learned about it?". Brain Pathology (Zurich, Switzerland). 31 (1): 20–32. doi:10.1111/bpa.12874. ISSN 1750-3639. PMC 8018001 Check
|pmc=value (help). PMID 32619305 Check|pmid=value (help). Check date values in:|date=(help) - ↑ 10.0 10.1 Kim, Young Zoon; et al. (2022-04). "The Overview of Practical Guidelines for Gliomas by KSNO, NCCN, and EANO". Brain Tumor Research and Treatment. 10 (2): 83–93. doi:10.14791/btrt.2022.0001. ISSN 2288-2405. PMC 9098981 Check
|pmc=value (help). PMID 35545827 Check|pmid=value (help). Check date values in:|date=(help) - ↑ Yamada S, Kipp BR, Voss JS, Giannini C, Raghunathan A. Combined "Infiltrating Astrocytoma/Pleomorphic Xanthoastrocytoma" Harboring IDH1 R132H and BRAF V600E Mutations. Am J Surg Pathol. 2016 Feb;40(2):279-84. doi: 10.1097/PAS.0000000000000515. PMID: 26414224.
- ↑ Fischer JM, Gilbert AR, Galvan EM, Singh AK, Floyd JR, Shah S. Pleomorphic xanthoastrocytoma with anaplasia and BEND5-NTRK2 fusion in a young adult with a history of cranial radiation for childhood rhabdomyosarcoma. Neurooncol Adv. 2025 Mar 8;7(1):vdaf052. doi: 10.1093/noajnl/vdaf052. PMID: 40568680; PMCID: PMC12188291.
- ↑ Martínez, Ramón; et al. (2014-03-20). "DNA methylation alterations in grade II- and anaplastic pleomorphic xanthoastrocytoma". BMC cancer. 14: 213. doi:10.1186/1471-2407-14-213. ISSN 1471-2407. PMC 4000050. PMID 24650279.
- ↑ Tang, Karen; et al. (2020-08-01). "Exploring DNA Methylation for Prognosis and Analyzing the Tumor Microenvironment in Pleomorphic Xanthoastrocytoma". Journal of Neuropathology and Experimental Neurology. 79 (8): 880–890. doi:10.1093/jnen/nlaa051. ISSN 1554-6578. PMC 8453609 Check
|pmc=value (help). PMID 32594172 Check|pmid=value (help). - ↑ https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2024.1268038/full
- ↑ Dampier, Christopher H.; et al. (2025). "Molecular, histologic, and clinical characterization of methylation class pleomorphic xanthoastrocytoma: An analysis of 469 tumors". Neuro-Oncology Advances. 7 (1): vdaf089. doi:10.1093/noajnl/vdaf089. ISSN 2632-2498. PMC 12305539 Check
|pmc=value (help). PMID 40735274 Check|pmid=value (help).
Notes
Khan WA: “Pleomorphic xanthoastrocytoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/25/2026, https://ccga.io/index.php/CNS5:Pleomorphic xanthoastrocytoma.