Recurrent copy number alterations in low-grade and anaplastic pleomorphic xanthoastrocytoma with and without BRAF V600E mutation

Rachael A. Vaubel, Alissa A. Caron, Seiji Yamada, Paul A. Decker, Jeanette E Eckel-Passow, Fausto J. Rodriguez, Amulya A. Nageswara Rao, Daniel H Lachance, Ian F Parney, Robert Brian Jenkins, Caterina Giannini

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Pleomorphic xanthoastrocytoma (PXA) is a rare localized glioma characterized by frequent BRAF V600E mutation and CDKN2A/B deletion. We explored the association of copy-number variants (CNVs) with BRAF mutations, tumor grade, and patient survival in a cohort of 41 PXA patients using OncoScan chromosomal microarray. Primary resection specimens were available in 38 cases, including 24 PXA and 14 anaplastic PXA (A-PXA), 23 BRAF V600E mutant tumors (61%). CNVs were identified in all cases and most frequently involved chromosome 9 with homozygous CDKN2A/B deletion (n=33, 87%), a higher proportion than previously detected by comparative genomic hybridization (50%-60%) (37). CDKN2A/B deletion was present in similar proportion of PXA (83%), A-PXA (93%), BRAF V600E (87%), and wild-type (87%) tumors. Whole chromosome gains/losses were frequent, including gains +7 (n=15), +2 (n=11), +5 (n=10), +21 (n=10), +20 (n=9), +12 (n=8), +15 (n=8), and losses -22 (n=11), -14 (n=7), -13 (n=5). Losses and copy-neutral loss of heterozygosity were significantly more common in A-PXA, involving chromosomes 22 (P=0.009) and 14 (P=0.03). Amplification of 8p and 12q was identified in a single tumor. Histologic grade was a robust predictor of overall survival (P=0.003), while other copy-number changes, including CDKN2A/B deletion, did not show significant association with survival. Distinct histologic patterns of anaplasia included increased mitotic activity in an otherwise classic PXA or associated with small cell, fibrillary, or epithelioid morphology, with loss of SMARCB1 expression in one case. In 10 cases, matched specimens were compared, including A-PXA with areas of distinct low- and high-grade morphology (n=2), matched primary/tumor recurrence (n=7), or both (n=1). Copy-number changes on recurrence/anaplastic transformation were complex and highly variable, from nearly identical profiles to numerous copy-number changes. Overall, we confirm CDKN2A/B deletion as key a feature of PXA not associated with tumor grade or BRAF mutation, but central to the underlying genetics of PXA.

Original languageEnglish (US)
JournalBrain Pathology
DOIs
StateAccepted/In press - 2017

Fingerprint

Mutation
Neoplasms
Survival
Anaplasia
Recurrence
Chromosomes, Human, Pair 22
Chromosomes, Human, Pair 9
Comparative Genomic Hybridization
Loss of Heterozygosity
Glioma
Chromosomes

Keywords

  • Anaplastic pleomorphic xanthoastrocytoma
  • BRAF
  • Glioma
  • Low-grade glioma
  • Pleomorphic xanthoastrocytoma

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neuroscience(all)
  • Clinical Neurology

Cite this

Recurrent copy number alterations in low-grade and anaplastic pleomorphic xanthoastrocytoma with and without BRAF V600E mutation. / Vaubel, Rachael A.; Caron, Alissa A.; Yamada, Seiji; Decker, Paul A.; Eckel-Passow, Jeanette E; Rodriguez, Fausto J.; Nageswara Rao, Amulya A.; Lachance, Daniel H; Parney, Ian F; Jenkins, Robert Brian; Giannini, Caterina.

In: Brain Pathology, 2017.

Research output: Contribution to journalArticle

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abstract = "Pleomorphic xanthoastrocytoma (PXA) is a rare localized glioma characterized by frequent BRAF V600E mutation and CDKN2A/B deletion. We explored the association of copy-number variants (CNVs) with BRAF mutations, tumor grade, and patient survival in a cohort of 41 PXA patients using OncoScan chromosomal microarray. Primary resection specimens were available in 38 cases, including 24 PXA and 14 anaplastic PXA (A-PXA), 23 BRAF V600E mutant tumors (61{\%}). CNVs were identified in all cases and most frequently involved chromosome 9 with homozygous CDKN2A/B deletion (n=33, 87{\%}), a higher proportion than previously detected by comparative genomic hybridization (50{\%}-60{\%}) (37). CDKN2A/B deletion was present in similar proportion of PXA (83{\%}), A-PXA (93{\%}), BRAF V600E (87{\%}), and wild-type (87{\%}) tumors. Whole chromosome gains/losses were frequent, including gains +7 (n=15), +2 (n=11), +5 (n=10), +21 (n=10), +20 (n=9), +12 (n=8), +15 (n=8), and losses -22 (n=11), -14 (n=7), -13 (n=5). Losses and copy-neutral loss of heterozygosity were significantly more common in A-PXA, involving chromosomes 22 (P=0.009) and 14 (P=0.03). Amplification of 8p and 12q was identified in a single tumor. Histologic grade was a robust predictor of overall survival (P=0.003), while other copy-number changes, including CDKN2A/B deletion, did not show significant association with survival. Distinct histologic patterns of anaplasia included increased mitotic activity in an otherwise classic PXA or associated with small cell, fibrillary, or epithelioid morphology, with loss of SMARCB1 expression in one case. In 10 cases, matched specimens were compared, including A-PXA with areas of distinct low- and high-grade morphology (n=2), matched primary/tumor recurrence (n=7), or both (n=1). Copy-number changes on recurrence/anaplastic transformation were complex and highly variable, from nearly identical profiles to numerous copy-number changes. Overall, we confirm CDKN2A/B deletion as key a feature of PXA not associated with tumor grade or BRAF mutation, but central to the underlying genetics of PXA.",
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author = "Vaubel, {Rachael A.} and Caron, {Alissa A.} and Seiji Yamada and Decker, {Paul A.} and Eckel-Passow, {Jeanette E} and Rodriguez, {Fausto J.} and {Nageswara Rao}, {Amulya A.} and Lachance, {Daniel H} and Parney, {Ian F} and Jenkins, {Robert Brian} and Caterina Giannini",
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T1 - Recurrent copy number alterations in low-grade and anaplastic pleomorphic xanthoastrocytoma with and without BRAF V600E mutation

AU - Vaubel, Rachael A.

AU - Caron, Alissa A.

AU - Yamada, Seiji

AU - Decker, Paul A.

AU - Eckel-Passow, Jeanette E

AU - Rodriguez, Fausto J.

AU - Nageswara Rao, Amulya A.

AU - Lachance, Daniel H

AU - Parney, Ian F

AU - Jenkins, Robert Brian

AU - Giannini, Caterina

PY - 2017

Y1 - 2017

N2 - Pleomorphic xanthoastrocytoma (PXA) is a rare localized glioma characterized by frequent BRAF V600E mutation and CDKN2A/B deletion. We explored the association of copy-number variants (CNVs) with BRAF mutations, tumor grade, and patient survival in a cohort of 41 PXA patients using OncoScan chromosomal microarray. Primary resection specimens were available in 38 cases, including 24 PXA and 14 anaplastic PXA (A-PXA), 23 BRAF V600E mutant tumors (61%). CNVs were identified in all cases and most frequently involved chromosome 9 with homozygous CDKN2A/B deletion (n=33, 87%), a higher proportion than previously detected by comparative genomic hybridization (50%-60%) (37). CDKN2A/B deletion was present in similar proportion of PXA (83%), A-PXA (93%), BRAF V600E (87%), and wild-type (87%) tumors. Whole chromosome gains/losses were frequent, including gains +7 (n=15), +2 (n=11), +5 (n=10), +21 (n=10), +20 (n=9), +12 (n=8), +15 (n=8), and losses -22 (n=11), -14 (n=7), -13 (n=5). Losses and copy-neutral loss of heterozygosity were significantly more common in A-PXA, involving chromosomes 22 (P=0.009) and 14 (P=0.03). Amplification of 8p and 12q was identified in a single tumor. Histologic grade was a robust predictor of overall survival (P=0.003), while other copy-number changes, including CDKN2A/B deletion, did not show significant association with survival. Distinct histologic patterns of anaplasia included increased mitotic activity in an otherwise classic PXA or associated with small cell, fibrillary, or epithelioid morphology, with loss of SMARCB1 expression in one case. In 10 cases, matched specimens were compared, including A-PXA with areas of distinct low- and high-grade morphology (n=2), matched primary/tumor recurrence (n=7), or both (n=1). Copy-number changes on recurrence/anaplastic transformation were complex and highly variable, from nearly identical profiles to numerous copy-number changes. Overall, we confirm CDKN2A/B deletion as key a feature of PXA not associated with tumor grade or BRAF mutation, but central to the underlying genetics of PXA.

AB - Pleomorphic xanthoastrocytoma (PXA) is a rare localized glioma characterized by frequent BRAF V600E mutation and CDKN2A/B deletion. We explored the association of copy-number variants (CNVs) with BRAF mutations, tumor grade, and patient survival in a cohort of 41 PXA patients using OncoScan chromosomal microarray. Primary resection specimens were available in 38 cases, including 24 PXA and 14 anaplastic PXA (A-PXA), 23 BRAF V600E mutant tumors (61%). CNVs were identified in all cases and most frequently involved chromosome 9 with homozygous CDKN2A/B deletion (n=33, 87%), a higher proportion than previously detected by comparative genomic hybridization (50%-60%) (37). CDKN2A/B deletion was present in similar proportion of PXA (83%), A-PXA (93%), BRAF V600E (87%), and wild-type (87%) tumors. Whole chromosome gains/losses were frequent, including gains +7 (n=15), +2 (n=11), +5 (n=10), +21 (n=10), +20 (n=9), +12 (n=8), +15 (n=8), and losses -22 (n=11), -14 (n=7), -13 (n=5). Losses and copy-neutral loss of heterozygosity were significantly more common in A-PXA, involving chromosomes 22 (P=0.009) and 14 (P=0.03). Amplification of 8p and 12q was identified in a single tumor. Histologic grade was a robust predictor of overall survival (P=0.003), while other copy-number changes, including CDKN2A/B deletion, did not show significant association with survival. Distinct histologic patterns of anaplasia included increased mitotic activity in an otherwise classic PXA or associated with small cell, fibrillary, or epithelioid morphology, with loss of SMARCB1 expression in one case. In 10 cases, matched specimens were compared, including A-PXA with areas of distinct low- and high-grade morphology (n=2), matched primary/tumor recurrence (n=7), or both (n=1). Copy-number changes on recurrence/anaplastic transformation were complex and highly variable, from nearly identical profiles to numerous copy-number changes. Overall, we confirm CDKN2A/B deletion as key a feature of PXA not associated with tumor grade or BRAF mutation, but central to the underlying genetics of PXA.

KW - Anaplastic pleomorphic xanthoastrocytoma

KW - BRAF

KW - Glioma

KW - Low-grade glioma

KW - Pleomorphic xanthoastrocytoma

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