CNS5:Pleomorphic xanthoastrocytoma

Central Nervous System Tumours (WHO Classification, 5th ed.)

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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

Acceptable	N/A
Not Recommended	Pleomorphic xanthoastrocytoma with anaplastic features; anaplastic pleomorphic xanthoastrocytoma (for CNS WHO grade 3)

Gene Rearrangements

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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)	BRAF p.V600E is diagnostic and predictive; kinase fusions targetable in rare cases
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)	P (poor; recurrence risk)	Yes (WHO, NCCN-context specefic)	Seen mainly in grade 3/anaplastic; adverse outcome
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%)	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

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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
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	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

Put your text here and fill in the table (Instructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

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
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
Complex karyotype with multiple CNVs	Chromosomal instability (CIN)	Common	P	No	Includes polyploidy, subclones, mosaicism; complexity increases at recurrence/progression
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)

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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
TERT	Promoter mutation	Other	Recurrent	P	Yes (WHO CNS5)	Associated with anaplastic progression, poor recurrence-free survival, and adverse prognosis in high-grade PXA (PMID: 35545827)
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 (PMID: 26414224)
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.(PMID: 40568680)

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.

Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations	EXAMPLE: Histone modification, chromatin remodeling	EXAMPLE: Abnormal gene expression program

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

Familial Forms

For most PXAs, no inherited/familial cause is identified, and they are considered sporadic tumors.

Additional Information

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Links

Pleomorphic Xanthoastrocytoma (PXA) and Other BRAF-Altered Tumors: Diagnosis and Treatment - NCI

References

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Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s): *Citation of this Page: “Pleomorphic xanthoastrocytoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/8/2026, https://ccga.io/index.php/CNS5:Pleomorphic xanthoastrocytoma.