Recurrent copy number alterations in low-grade and anaplastic pleomorphic xanthoastrocytoma with and without BRAF V600E mutation.
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.
From the Departments of Anatomic Pathology, Mayo Clinic, Rochester, MN.
Rachael A
0000-0001-8842-5975
RA
Vaubel
Experimental Pathology, Mayo Clinic, Rochester, MN.
Alissa A
AA
Caron
Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan.
Seiji
S
Yamada
Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN.
Paul A
PA
Decker
Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN.
Jeanette E
JE
Eckel Passow
Department of Pathology, Johns Hopkins Hospital, Baltimore, MD.
Fausto J
FJ
Rodriguez
Pediatric Hematology-Oncology, Mayo Clinic, Rochester, MN.
Amulya A
AA
Nageswara Rao
Neurology, Mayo Clinic, Rochester, MN.
Daniel
D
Lachance
Neurologic Surgery, Mayo Clinic, Rochester, MN.
Ian
I
Parney
Cytogenetics Laboratory, Mayo Clinic, Rochester, MN.
Robert
R
Jenkins
From the Departments of Anatomic Pathology, Mayo Clinic, Rochester, MN.
Caterina
C
Giannini
D000293:Adolescent; D000328:Adult; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D056915:DNA Copy Number Variations; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D000071796:SMARCB1 Protein / Q000378:metabolism; D015173:Supratentorial Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D055815:Young Adult
C000614131:CDKN2A protein, human; C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
BRAF; anaplastic pleomorphic xanthoastrocytoma; glioma; low-grade glioma; pleomorphic xanthoastrocytoma