Molecular, histologic, and clinical characterization of methylation class pleomorphic xanthoastrocytoma: An analysis of 469 tumors

Christopher H. Dampier; Niharika Shah; Kristyn Galbraith; Azadeh Ebrahimi; Osorio Lopes Abath Neto; Zied Abdullaev; Sanda Alexandrescu; Felipe Andreiuolo; Terri Armstrong; Tiffany Baker; Sahara Cathcart; Hye Jung Chung; Patrick J. Cimino; Kyle S. Conway; Jennifer Cotter; Felipe D'Almeida Costa; Karen Dazelle; Nima Etminam; Sima Esther Ferman; Igor Fernandes; Christina K. Ferrone; Ahmed Gilani; Mark Gilbert; Jason Gregory; Courtney Ketchum; Han Sung Lee; Ina Lee; Maria Beatriz S. Lopes; Qinwen Mao; Michael S. Marshall; Matthew McCord; Stewart G. Neill; Jeffrey J. Nirschl; Byram H. Ozer; Werner Paulus; Marta Penas-Prado; Marco Prinz; Peter Pytel; Martha Quezado; Mark Raffeld; Sharika Rajan; Miriam Ratliff; Guido Reifenberger; Lorraina Robinson; Jens Schittenhelm; Daniel Schrimpf; Omkar Singh; Christian Thomas; Diana Thomas; Jaiyeola Thomas-Ogunniyi; Angus Toland; Rust Turakulov; Rachael Vaubel; Nitin Wadhwani; Jing Wu; Caterina Giannini; Matija Snuderl; Sebastian Brandner; Andreas von Deimling; Kenneth Aldape

doi:10.1093/noajnl/vdaf089

Molecular, histologic, and clinical characterization of methylation class pleomorphic xanthoastrocytoma: An analysis of 469 tumors

Christopher H. Dampier, Niharika Shah, Kristyn Galbraith, Azadeh Ebrahimi, Osorio Lopes Abath Neto, Zied Abdullaev, Sanda Alexandrescu, Felipe Andreiuolo, Terri Armstrong, Tiffany Baker, Sahara Cathcart, Hye Jung Chung, Patrick J. Cimino, Kyle S. Conway, Jennifer Cotter, Felipe D'Almeida Costa, Karen Dazelle, Nima Etminam, Sima Esther Ferman, Igor FernandesChristina K. Ferrone, Ahmed Gilani, Mark Gilbert, Jason Gregory, Courtney Ketchum, Han Sung Lee, Ina Lee, Maria Beatriz S. Lopes, Qinwen Mao, Michael S. Marshall, Matthew McCord, Stewart G. Neill, Jeffrey J. Nirschl, Byram H. Ozer, Werner Paulus, Marta Penas-Prado, Marco Prinz, Peter Pytel, Martha Quezado, Mark Raffeld, Sharika Rajan, Miriam Ratliff, Guido Reifenberger, Lorraina Robinson, Jens Schittenhelm, Daniel Schrimpf, Omkar Singh, Christian Thomas, Diana Thomas, Jaiyeola Thomas-Ogunniyi, Angus Toland, Rust Turakulov, Rachael Vaubel, Nitin Wadhwani, Jing Wu, Caterina Giannini, Matija Snuderl, Sebastian Brandner, Andreas von Deimling, Kenneth Aldape^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Background. Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the DNA methylation signature of classical PXA but with a wider histologic spectrum, including overlap with glioblastoma (GBM). Methods. To clarify the histologic and molecular scope of mcPXA and characterize its clinical behavior, a cohort of 469 tumor samples from 458 patients matching to mcPXA by the DKFZ classifier (v12.6 score ≥0.85) was interrogated. Results. Patient median age was 23 years (range 1-73 years) with a female predominance (259 female/199 male). CDKN2A/B homozygous deletion was observed in 406 of 469 (87%) samples. In samples tested for BRAF p.V600E mutations (n = 279), 240 (86%) harbored the mutation. A chr7+/chr10− pattern was observed in 103 of 469 (22%) samples. Among samples tested for TERT promoter mutations (n = 143), 32 (22%) harbored the mutation. Progression-free and overall survival of patients with mcPXA were comparable to patients with methylation class IDH-mutant astrocytoma, low grade, but a GBM-like subset (ie, cases with a pre-methylation working diagnosis of GBM) showed shorter survival. Histologic features of high grade, including palisading necrosis and microvascular proliferation, were prognostic in mcPXA. Compared to patients with BRAF p.V600E-altered GBM, patients with mcPXA were younger and had a lower frequency of TERT promoter mutations. Conclusion. Tumors in mcPXA share molecular characteristics with histologically defined PXA, and high-grade histologic features can help predict their clinical behavior. The use of an epigenetic classification of PXA reveals that this group of tumors is more common than previously appreciated and warrants in-depth study to identify efficacious therapeutic options.

Original language	English (US)
Article number	vdaf089
Journal	Neuro-Oncology Advances
Volume	7
Issue number	1
DOIs	https://doi.org/10.1093/noajnl/vdaf089
State	Published - Jan 1 2025
Externally published	Yes

Funding

Microarray and whole slide image data were obtained from University College London Hospitals NHS Foundation Trust as part of BRAIN UK, which is supported by Brain Tumor Research and has been established with the support of the British Neuropathological Society and the Medical Research Council. The results shown here are in part based upon data generated by the TCGA Research Network ( http://cancergenome.nih.gov ). This work utilized the computational resources of the NIH HPC Biowulf cluster ( https://hpc.nih.gov ). This work was supported by the intramural research program of the National Cancer Institute, National Institutes of Health. Microarray and whole slide image data were obtained fromUniversity College London Hospitals NHS Foundation Trust aspart of BRAIN UK, which is supported by Brain Tumor Researchand has been established with the support of the BritishNeuropathological Society and the Medical Research Council.The results shown here are in part based upon data generatedby the TCGA Research Network (http://cancergenome.nih.gov).This work utilized the computational resources of the NIH HPCBiowulf cluster (https://hpc.nih.gov).

Keywords

BRAF p.V600E
CDKN2A/B deletion
DNA methylation classification
epithelioid glioblastoma
pleomorphic xanthoastrocytoma

ASJC Scopus subject areas

Surgery
Oncology
Clinical Neurology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/noajnl/vdaf089

Cite this

Dampier, C. H., Shah, N., Galbraith, K., Ebrahimi, A., Neto, O. L. A., Abdullaev, Z., Alexandrescu, S., Andreiuolo, F., Armstrong, T., Baker, T., Cathcart, S., Chung, H. J., Cimino, P. J., Conway, K. S., Cotter, J., D'Almeida Costa, F., Dazelle, K., Etminam, N., Ferman, S. E., ... Aldape, K. (2025). Molecular, histologic, and clinical characterization of methylation class pleomorphic xanthoastrocytoma: An analysis of 469 tumors. Neuro-Oncology Advances, 7(1), Article vdaf089. https://doi.org/10.1093/noajnl/vdaf089

@article{4cd8ed8bf1a342ecafba09728013b7ed,

title = "Molecular, histologic, and clinical characterization of methylation class pleomorphic xanthoastrocytoma: An analysis of 469 tumors",

abstract = "Background. Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the DNA methylation signature of classical PXA but with a wider histologic spectrum, including overlap with glioblastoma (GBM). Methods. To clarify the histologic and molecular scope of mcPXA and characterize its clinical behavior, a cohort of 469 tumor samples from 458 patients matching to mcPXA by the DKFZ classifier (v12.6 score ≥0.85) was interrogated. Results. Patient median age was 23 years (range 1-73 years) with a female predominance (259 female/199 male). CDKN2A/B homozygous deletion was observed in 406 of 469 (87\%) samples. In samples tested for BRAF p.V600E mutations (n = 279), 240 (86\%) harbored the mutation. A chr7+/chr10− pattern was observed in 103 of 469 (22\%) samples. Among samples tested for TERT promoter mutations (n = 143), 32 (22\%) harbored the mutation. Progression-free and overall survival of patients with mcPXA were comparable to patients with methylation class IDH-mutant astrocytoma, low grade, but a GBM-like subset (ie, cases with a pre-methylation working diagnosis of GBM) showed shorter survival. Histologic features of high grade, including palisading necrosis and microvascular proliferation, were prognostic in mcPXA. Compared to patients with BRAF p.V600E-altered GBM, patients with mcPXA were younger and had a lower frequency of TERT promoter mutations. Conclusion. Tumors in mcPXA share molecular characteristics with histologically defined PXA, and high-grade histologic features can help predict their clinical behavior. The use of an epigenetic classification of PXA reveals that this group of tumors is more common than previously appreciated and warrants in-depth study to identify efficacious therapeutic options.",

keywords = "BRAF p.V600E, CDKN2A/B deletion, DNA methylation classification, epithelioid glioblastoma, pleomorphic xanthoastrocytoma",

author = "Dampier, \{Christopher H.\} and Niharika Shah and Kristyn Galbraith and Azadeh Ebrahimi and Neto, \{Osorio Lopes Abath\} and Zied Abdullaev and Sanda Alexandrescu and Felipe Andreiuolo and Terri Armstrong and Tiffany Baker and Sahara Cathcart and Chung, \{Hye Jung\} and Cimino, \{Patrick J.\} and Conway, \{Kyle S.\} and Jennifer Cotter and \{D'Almeida Costa\}, Felipe and Karen Dazelle and Nima Etminam and Ferman, \{Sima Esther\} and Igor Fernandes and Ferrone, \{Christina K.\} and Ahmed Gilani and Mark Gilbert and Jason Gregory and Courtney Ketchum and Lee, \{Han Sung\} and Ina Lee and Lopes, \{Maria Beatriz S.\} and Qinwen Mao and Marshall, \{Michael S.\} and Matthew McCord and Neill, \{Stewart G.\} and Nirschl, \{Jeffrey J.\} and Ozer, \{Byram H.\} and Werner Paulus and Marta Penas-Prado and Marco Prinz and Peter Pytel and Martha Quezado and Mark Raffeld and Sharika Rajan and Miriam Ratliff and Guido Reifenberger and Lorraina Robinson and Jens Schittenhelm and Daniel Schrimpf and Omkar Singh and Christian Thomas and Diana Thomas and Jaiyeola Thomas-Ogunniyi and Angus Toland and Rust Turakulov and Rachael Vaubel and Nitin Wadhwani and Jing Wu and Caterina Giannini and Matija Snuderl and Sebastian Brandner and \{von Deimling\}, Andreas and Kenneth Aldape",

note = "Publisher Copyright: {\textcopyright} 2025 Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology 2025.",

year = "2025",

month = jan,

day = "1",

doi = "10.1093/noajnl/vdaf089",

language = "English (US)",

volume = "7",

journal = "Neuro-Oncology Advances",

issn = "2632-2498",

publisher = "Oxford University Press",

number = "1",

}

Dampier, CH, Shah, N, Galbraith, K, Ebrahimi, A, Neto, OLA, Abdullaev, Z, Alexandrescu, S, Andreiuolo, F, Armstrong, T, Baker, T, Cathcart, S, Chung, HJ, Cimino, PJ, Conway, KS, Cotter, J, D'Almeida Costa, F, Dazelle, K, Etminam, N, Ferman, SE, Fernandes, I, Ferrone, CK, Gilani, A, Gilbert, M, Gregory, J, Ketchum, C, Lee, HS, Lee, I, Lopes, MBS, Mao, Q, Marshall, MS, McCord, M, Neill, SG, Nirschl, JJ, Ozer, BH, Paulus, W, Penas-Prado, M, Prinz, M, Pytel, P, Quezado, M, Raffeld, M, Rajan, S, Ratliff, M, Reifenberger, G, Robinson, L, Schittenhelm, J, Schrimpf, D, Singh, O, Thomas, C, Thomas, D, Thomas-Ogunniyi, J, Toland, A, Turakulov, R, Vaubel, R, Wadhwani, N, Wu, J, Giannini, C, Snuderl, M, Brandner, S, von Deimling, A & Aldape, K 2025, 'Molecular, histologic, and clinical characterization of methylation class pleomorphic xanthoastrocytoma: An analysis of 469 tumors', Neuro-Oncology Advances, vol. 7, no. 1, vdaf089. https://doi.org/10.1093/noajnl/vdaf089

TY - JOUR

T1 - Molecular, histologic, and clinical characterization of methylation class pleomorphic xanthoastrocytoma

T2 - An analysis of 469 tumors

AU - Dampier, Christopher H.

AU - Shah, Niharika

AU - Galbraith, Kristyn

AU - Ebrahimi, Azadeh

AU - Neto, Osorio Lopes Abath

AU - Abdullaev, Zied

AU - Alexandrescu, Sanda

AU - Andreiuolo, Felipe

AU - Armstrong, Terri

AU - Baker, Tiffany

AU - Cathcart, Sahara

AU - Chung, Hye Jung

AU - Cimino, Patrick J.

AU - Conway, Kyle S.

AU - Cotter, Jennifer

AU - D'Almeida Costa, Felipe

AU - Dazelle, Karen

AU - Etminam, Nima

AU - Ferman, Sima Esther

AU - Fernandes, Igor

AU - Ferrone, Christina K.

AU - Gilani, Ahmed

AU - Gilbert, Mark

AU - Gregory, Jason

AU - Ketchum, Courtney

AU - Lee, Han Sung

AU - Lee, Ina

AU - Lopes, Maria Beatriz S.

AU - Mao, Qinwen

AU - Marshall, Michael S.

AU - McCord, Matthew

AU - Neill, Stewart G.

AU - Nirschl, Jeffrey J.

AU - Ozer, Byram H.

AU - Paulus, Werner

AU - Penas-Prado, Marta

AU - Prinz, Marco

AU - Pytel, Peter

AU - Quezado, Martha

AU - Raffeld, Mark

AU - Rajan, Sharika

AU - Ratliff, Miriam

AU - Reifenberger, Guido

AU - Robinson, Lorraina

AU - Schittenhelm, Jens

AU - Schrimpf, Daniel

AU - Singh, Omkar

AU - Thomas, Christian

AU - Thomas, Diana

AU - Thomas-Ogunniyi, Jaiyeola

AU - Toland, Angus

AU - Turakulov, Rust

AU - Vaubel, Rachael

AU - Wadhwani, Nitin

AU - Wu, Jing

AU - Giannini, Caterina

AU - Snuderl, Matija

AU - Brandner, Sebastian

AU - von Deimling, Andreas

AU - Aldape, Kenneth

PY - 2025/1/1

Y1 - 2025/1/1

N2 - Background. Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the DNA methylation signature of classical PXA but with a wider histologic spectrum, including overlap with glioblastoma (GBM). Methods. To clarify the histologic and molecular scope of mcPXA and characterize its clinical behavior, a cohort of 469 tumor samples from 458 patients matching to mcPXA by the DKFZ classifier (v12.6 score ≥0.85) was interrogated. Results. Patient median age was 23 years (range 1-73 years) with a female predominance (259 female/199 male). CDKN2A/B homozygous deletion was observed in 406 of 469 (87%) samples. In samples tested for BRAF p.V600E mutations (n = 279), 240 (86%) harbored the mutation. A chr7+/chr10− pattern was observed in 103 of 469 (22%) samples. Among samples tested for TERT promoter mutations (n = 143), 32 (22%) harbored the mutation. Progression-free and overall survival of patients with mcPXA were comparable to patients with methylation class IDH-mutant astrocytoma, low grade, but a GBM-like subset (ie, cases with a pre-methylation working diagnosis of GBM) showed shorter survival. Histologic features of high grade, including palisading necrosis and microvascular proliferation, were prognostic in mcPXA. Compared to patients with BRAF p.V600E-altered GBM, patients with mcPXA were younger and had a lower frequency of TERT promoter mutations. Conclusion. Tumors in mcPXA share molecular characteristics with histologically defined PXA, and high-grade histologic features can help predict their clinical behavior. The use of an epigenetic classification of PXA reveals that this group of tumors is more common than previously appreciated and warrants in-depth study to identify efficacious therapeutic options.

AB - Background. Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the DNA methylation signature of classical PXA but with a wider histologic spectrum, including overlap with glioblastoma (GBM). Methods. To clarify the histologic and molecular scope of mcPXA and characterize its clinical behavior, a cohort of 469 tumor samples from 458 patients matching to mcPXA by the DKFZ classifier (v12.6 score ≥0.85) was interrogated. Results. Patient median age was 23 years (range 1-73 years) with a female predominance (259 female/199 male). CDKN2A/B homozygous deletion was observed in 406 of 469 (87%) samples. In samples tested for BRAF p.V600E mutations (n = 279), 240 (86%) harbored the mutation. A chr7+/chr10− pattern was observed in 103 of 469 (22%) samples. Among samples tested for TERT promoter mutations (n = 143), 32 (22%) harbored the mutation. Progression-free and overall survival of patients with mcPXA were comparable to patients with methylation class IDH-mutant astrocytoma, low grade, but a GBM-like subset (ie, cases with a pre-methylation working diagnosis of GBM) showed shorter survival. Histologic features of high grade, including palisading necrosis and microvascular proliferation, were prognostic in mcPXA. Compared to patients with BRAF p.V600E-altered GBM, patients with mcPXA were younger and had a lower frequency of TERT promoter mutations. Conclusion. Tumors in mcPXA share molecular characteristics with histologically defined PXA, and high-grade histologic features can help predict their clinical behavior. The use of an epigenetic classification of PXA reveals that this group of tumors is more common than previously appreciated and warrants in-depth study to identify efficacious therapeutic options.

KW - BRAF p.V600E

KW - CDKN2A/B deletion

KW - DNA methylation classification

KW - epithelioid glioblastoma

KW - pleomorphic xanthoastrocytoma

UR - https://www.scopus.com/pages/publications/105012216753

UR - https://www.scopus.com/inward/citedby.url?scp=105012216753&partnerID=8YFLogxK

U2 - 10.1093/noajnl/vdaf089

DO - 10.1093/noajnl/vdaf089

M3 - Article

C2 - 40735274

AN - SCOPUS:105012216753

SN - 2632-2498

VL - 7

JO - Neuro-Oncology Advances

JF - Neuro-Oncology Advances

IS - 1

M1 - vdaf089

ER -

Molecular, histologic, and clinical characterization of methylation class pleomorphic xanthoastrocytoma: An analysis of 469 tumors

Abstract

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ASJC Scopus subject areas

UN SDGs

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