CNS5:Pleomorphic xanthoastrocytoma: Difference between revisions

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{{DISPLAYTITLE:Pleomorphic xanthoastrocytoma}}


[[CNS5:Table_of_Contents|Central Nervous System Tumours (WHO Classification, 5th ed.)]]
<span style="color:#0070C0">(''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).'' </span>
==Primary Author(s)*==
==Primary Author(s)*==
Wahab A. Khan, PhD, FACMG, Dartmouth Health <span style="color:#0070C0"> </span>
==WHO Classification of Disease==


__TOC__
{| class="wikitable"
 
!Structure
==Cancer Category/Type==
!Disease
 
Put your text here
 
==Cancer Sub-Classification / Subtype==
 
Put your text here
 
==Definition / Description of Disease==
 
Put your text here
 
==Synonyms / Terminology==
 
Put your text here
 
==Epidemiology / Prevalence==
 
Put your text here
 
==Clinical Features==
 
Put your text here
 
==Sites of Involvement==
 
Put your text here
 
==Morphologic Features==
 
Put your text here
 
==Immunophenotype==
 
Put your text here and/or fill in the table
 
{| class="wikitable sortable"
|-
|-
! Finding  !! Marker
|Book
|Central Nervous System Tumours (5th ed.)
|-
|-
|Positive (universal) || EXAMPLE CD1
|Category
|Gliomas, glioneuronal tumours, and neuronal tumours
|-
|-
|Positive (subset) || EXAMPLE CD2
|Family
|Gliomas, glioneuronal tumours, and neuronal tumours
|-
|-
|Negative (universal) || EXAMPLE CD3
|Type
|Circumscribed astrocytic gliomas
|-
|-
|Negative (subset) || EXAMPLE CD4
|Subtype(s)
|Pleomorphic xanthoastrocytoma
|}
|}


==Chromosomal Rearrangements (Gene Fusions)==
== Related Terminology - Pleomorphic xanthoastrocytoma (PXA) ==
 
{| class="wikitable"
|+
|Acceptable
|N/A
|-
|Not Recommended
|Pleomorphic xanthoastrocytoma with anaplastic features; anaplastic pleomorphic xanthoastrocytoma (for CNS WHO grade 3)
|}


Put your text here and/or fill in the table
==Gene Rearrangements ==


{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
! Chromosomal Rearrangement !! Genes in Fusion (5’ or 3’ Segments) !! Pathogenic Derivative !! Prevalence
!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
|-
|-
|EXAMPLE t(9;22)(q34;q11.2) || EXAMPLE 3'ABL1 / 5'BCR || EXAMPLE der(22) || EXAMPLE 5%
|''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)<ref>{{Cite journal|last=d’Amati|first=Antonio|last2=Bargiacchi|first2=Lavinia|last3=Rossi|first3=Sabrina|last4=Carai|first4=Andrea|last5=Bertero|first5=Luca|last6=Barresi|first6=Valeria|last7=Errico|first7=Maria Elena|last8=Buccoliero|first8=Anna Maria|last9=Asioli|first9=Sofia|date=2024-03-13|title=Pediatric CNS tumors and 2021 WHO classification: what do oncologists need from pathologists?|url=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2024.1268038/full|journal=Frontiers in Molecular Neuroscience|language=English|volume=17|doi=10.3389/fnmol.2024.1268038|issn=1662-5099}}</ref>
|BRAF p.V600E is diagnostic and predictive; kinase fusions targetable in rare cases<ref name=":0">{{Cite journal|last=Phillips|first=Joanna J.|last2=Gong|first2=Henry|last3=Chen|first3=Katharine|last4=Joseph|first4=Nancy M.|last5=van Ziffle|first5=Jessica|last6=Bastian|first6=Boris C.|last7=Grenert|first7=James P.|last8=Kline|first8=Cassie N.|last9=Mueller|first9=Sabine|date=2019-01|title=The genetic landscape of anaplastic pleomorphic xanthoastrocytoma|url=https://pubmed.ncbi.nlm.nih.gov/30051528|journal=Brain Pathology (Zurich, Switzerland)|volume=29|issue=1|pages=85–96|doi=10.1111/bpa.12639|issn=1750-3639|pmc=7837273|pmid=30051528}}</ref><ref>{{Cite journal|last=Vaubel|first=Rachael A.|last2=Caron|first2=Alissa A.|last3=Yamada|first3=Seiji|last4=Decker|first4=Paul A.|last5=Eckel Passow|first5=Jeanette E.|last6=Rodriguez|first6=Fausto J.|last7=Nageswara Rao|first7=Amulya A.|last8=Lachance|first8=Daniel|last9=Parney|first9=Ian|date=2018-03|title=Recurrent copy number alterations in low-grade and anaplastic pleomorphic xanthoastrocytoma with and without BRAF V600E mutation|url=https://pmc.ncbi.nlm.nih.gov/articles/PMC5807227/|journal=Brain Pathology (Zurich, Switzerland)|volume=28|issue=2|pages=172–182|doi=10.1111/bpa.12495|issn=1750-3639|pmc=5807227|pmid=28181325}}</ref> <ref>{{Cite journal|last=Tian|first=Lei|last2=Sun|first2=Wei|last3=Lou|first3=Lei|last4=Wang|first4=Wenyan|last5=Li|first5=Yanan|last6=Zhou|first6=Huandi|last7=Xiao|first7=Zhiqing|last8=Xue|first8=Xiaoying|date=2025|title=Pleomorphic xanthoastrocytoma with multiple recurrences and continuous malignant progression to bone metastasis: a case report|url=https://pmc.ncbi.nlm.nih.gov/articles/PMC12174448/|journal=Frontiers in Surgery|volume=12|pages=1595199|doi=10.3389/fsurg.2025.1595199|issn=2296-875X|pmc=12174448|pmid=40535548}}</ref><ref>{{Cite journal|last=Di Nunno|first=Vincenzo|last2=Gatto|first2=Lidia|last3=Tosoni|first3=Alicia|last4=Bartolini|first4=Stefania|last5=Franceschi|first5=Enrico|date=2022|title=Implications of BRAF V600E mutation in gliomas: Molecular considerations, prognostic value and treatment evolution|url=https://pmc.ncbi.nlm.nih.gov/articles/PMC9846085/|journal=Frontiers in Oncology|volume=12|pages=1067252|doi=10.3389/fonc.2022.1067252|issn=2234-943X|pmc=9846085|pmid=36686797}}</ref>
|-
|-
|EXAMPLE t(8;21)(q22;q22) || EXAMPLE 5'RUNX1 / 3'RUNXT1 || EXAMPLE der(8) || EXAMPLE 5%
|''CDKN2A''/''B''
|}
|N/A
|Loss leads to cell cycle dysregulation
==Characteristic Chromosomal Aberrations / Patterns==
|''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


Put your text here
|Telomerase activation (mainly in anaplastic PXA)
|TERT promoter mutations/amplifications
|Recurrent (15–47% in anaplastic)<ref>{{Cite journal|last=Phillips|first=Joanna J.|last2=Gong|first2=Henry|last3=Chen|first3=Katharine|last4=Joseph|first4=Nancy M.|last5=van Ziffle|first5=Jessica|last6=Bastian|first6=Boris C.|last7=Grenert|first7=James P.|last8=Kline|first8=Cassie N.|last9=Mueller|first9=Sabine|date=2019-01|title=The genetic landscape of anaplastic pleomorphic xanthoastrocytoma|url=https://pubmed.ncbi.nlm.nih.gov/30051528|journal=Brain Pathology (Zurich, Switzerland)|volume=29|issue=1|pages=85–96|doi=10.1111/bpa.12639|issn=1750-3639|pmc=7837273|pmid=30051528}}</ref>
|P (poor; recurrence risk)
|Yes (WHO, NCCN-context specefic)
|Seen mainly in grade 3/anaplastic; adverse outcome<ref name=":0" />


==Genomic Gain/Loss/LOH==
<br />
 
|-
Put your text here and/or fill in the table
|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%)<ref>{{Cite journal|last=Galbraith|first=Kristyn|last2=Serrano|first2=Jonathan|last3=Shen|first3=Guomiao|last4=Tran|first4=Ivy|last5=Slocum|first5=Cheyanne C.|last6=Ketchum|first6=Courtney|last7=Abdullaev|first7=Zied|last8=Turakulov|first8=Rust|last9=Bale|first9=Tejus|date=2024-01-02|title=Impact of Rare and Multiple Concurrent Gene Fusions on Diagnostic DNA Methylation Classifier in Brain Tumors|url=https://pubmed.ncbi.nlm.nih.gov/37870438|journal=Molecular cancer research: MCR|volume=22|issue=1|pages=21–28|doi=10.1158/1541-7786.MCR-23-0627|issn=1557-3125|pmc=10942665|pmid=37870438}}</ref>
|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==


{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
! Chromosome Number !! Gain/Loss/Amp/LOH !! Region
!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<ref name=":1" />
|-
|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<ref>{{Cite journal|last=Vaubel|first=Rachael|last2=Zschernack|first2=Valentina|last3=Tran|first3=Quynh T.|last4=Jenkins|first4=Sarah|last5=Caron|first5=Alissa|last6=Milosevic|first6=Dragana|last7=Smadbeck|first7=James|last8=Vasmatzis|first8=George|last9=Kandels|first9=Daniela|date=2021-01|title=Biology and grading of pleomorphic xanthoastrocytoma-what have we learned about it?|url=https://pmc.ncbi.nlm.nih.gov/articles/PMC8018001/|journal=Brain Pathology (Zurich, Switzerland)|volume=31|issue=1|pages=20–32|doi=10.1111/bpa.12874|issn=1750-3639|pmc=8018001|pmid=32619305}}</ref>
|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
|-
|-
|EXAMPLE 8 || EXAMPLE Gain || EXAMPLE chr8:0-1000000
|8p
|Loss
|chr 8p (varied region)
|Varies
|P
|No
|Seen in a subset, less common
|-
|-
|EXAMPLE 7 || EXAMPLE Loss || EXAMPLE chr7:0-1000000
|LOH
|}
|Copy-neutral
|Varies (mainly 9p21)
==Gene Mutations (SNV/INDEL)==
|CDKN2A, CDKN2B
 
|D, P
Put your text here and/or fill in the tables
|Yes (NCCN)
|copy-neutral LOH; supports diagnosis
|}
==Characteristic Chromosomal or Other Global Mutational Patterns==


{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
! Gene !! Mutation !! Oncogene/Tumor Suppressor/Other !! Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) !! Prevalence (COSMIC/TCGA/Other)
!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<ref name=":1">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.</ref>
|-
|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<ref name=":1" />
|-
|Complex karyotype with multiple CNVs
|Chromosomal instability (CIN)
|Common
|P
|No
|Includes polyploidy, subclones, mosaicism; complexity increases at recurrence/progression<ref name=":1" />
|-
|-
| EXAMPLE TP53 || EXAMPLE R273H || EXAMPLE Tumor Suppressor || EXAMPLE LOF || EXAMPLE 20%
|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
===Other Mutations===
|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)==
<span style="color:#0070C0">''This table is not meant to be an exhaustive list''</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
! Type !! Gene/Region/Other
!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
 
<br />
|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<ref name=":2">{{Cite journal|last=Kim|first=Young Zoon|last2=Kim|first2=Chae-Yong|last3=Lim|first3=Do Hoon|date=2022-04|title=The Overview of Practical Guidelines for Gliomas by KSNO, NCCN, and EANO|url=https://pubmed.ncbi.nlm.nih.gov/35545827|journal=Brain Tumor Research and Treatment|volume=10|issue=2|pages=83–93|doi=10.14791/btrt.2022.0001|issn=2288-2405|pmc=9098981|pmid=35545827}}</ref>
|-
|-
| Concomitant Mutations || EXAMPLE IDH1 R123H
|TERT
<br />
|Promoter mutation
|Other
|Recurrent
|P
|Yes (WHO CNS5)
|Associated with anaplastic progression, poor recurrence-free survival, and adverse prognosis in high-grade PXA<ref name=":2" />
|-
|-
| Secondary Mutations || EXAMPLE Trisomy 7
|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<ref>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.</ref>
|-
|-
|Mutually Exclusive || EXAMPLE EGFR Amplification
|NTRK2, ALK
|}
|Kinase gene fusions
 
|Oncogene
==Epigenomics (Methylation)==
|Rare
 
|T
Put your text here
|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<ref>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.</ref>
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], 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<ref>{{Cite journal|last=Martínez|first=Ramón|last2=Carmona|first2=F. Javier|last3=Vizoso|first3=Miguel|last4=Rohde|first4=Veit|last5=Kirsch|first5=Matthias|last6=Schackert|first6=Gabriele|last7=Ropero|first7=Santiago|last8=Paulus|first8=Werner|last9=Barrantes|first9=Alonso|date=2014-03-20|title=DNA methylation alterations in grade II- and anaplastic pleomorphic xanthoastrocytoma|url=https://pubmed.ncbi.nlm.nih.gov/24650279|journal=BMC cancer|volume=14|pages=213|doi=10.1186/1471-2407-14-213|issn=1471-2407|pmc=4000050|pmid=24650279}}</ref><ref>{{Cite journal|last=Tang|first=Karen|last2=Kurland|first2=David|last3=Vasudevaraja|first3=Varshini|last4=Serrano|first4=Jonathan|last5=Delorenzo|first5=Michael|last6=Radmanesh|first6=Alireza|last7=Thomas|first7=Cheddhi|last8=Spino|first8=Marissa|last9=Gardner|first9=Sharon|date=2020-08-01|title=Exploring DNA Methylation for Prognosis and Analyzing the Tumor Microenvironment in Pleomorphic Xanthoastrocytoma|url=https://pmc.ncbi.nlm.nih.gov/articles/PMC8453609/|journal=Journal of Neuropathology and Experimental Neurology|volume=79|issue=8|pages=880–890|doi=10.1093/jnen/nlaa051|issn=1554-6578|pmc=8453609|pmid=32594172}}</ref>.


==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==


Put your text here
{| class="wikitable sortable"
 
|-
==Diagnostic Testing Methods==
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
|-
Put your text here
|''BRAF'' and ''MAP2K1''; Activating mutations
 
|MAPK signaling
==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==
|Increased cell growth and proliferation
 
|-
Put your text here
|''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<ref>https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2024.1268038/full</ref>
==Familial Forms==
==Familial Forms==
 
For most PXAs, no inherited/familial cause is identified, and they are considered sporadic tumors.
Put your text here
==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<ref>{{Cite journal|last=Dampier|first=Christopher H.|last2=Shah|first2=Niharika|last3=Galbraith|first3=Kristyn|last4=Ebrahimi|first4=Azadeh|last5=Neto|first5=Osorio Lopes Abath|last6=Abdullaev|first6=Zied|last7=Alexandrescu|first7=Sanda|last8=Andreiuolo|first8=Felipe|last9=Armstrong|first9=Terri|date=2025|title=Molecular, histologic, and clinical characterization of methylation class pleomorphic xanthoastrocytoma: An analysis of 469 tumors|url=https://pubmed.ncbi.nlm.nih.gov/40735274|journal=Neuro-Oncology Advances|volume=7|issue=1|pages=vdaf089|doi=10.1093/noajnl/vdaf089|issn=2632-2498|pmc=12305539|pmid=40735274}}</ref>.
==Other Information==
 
Put your text here


==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]
Put your links here
 
==References==
==References==
<references />


=== EXAMPLE Book ===
==Notes==
#Arber DA, et al., (2008). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4thedition.Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p117-118.
Khan WA: “Pleomorphic xanthoastrocytoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/CNS5:Pleomorphic xanthoastrocytoma</nowiki>.
 
[[Category:CNS5]]
=== EXAMPLE Journal Article ===
[[Category:DISEASE]]
#Li Y, et al., (2001). Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat Genet 28:220-221, PMID 11431691.
[[Category:Diseases P]]
 
== Notes ==
<nowiki>*</nowiki>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 CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.

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

  1. ↑ 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. ↑ 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)
  3. ↑ 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)
  4. ↑ 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).
  5. ↑ 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).
  6. ↑ 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)
  7. ↑ 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. ↑ 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.
  9. ↑ 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. ↑ 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)
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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).
  15. ↑ https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2024.1268038/full
  16. ↑ 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.

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