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

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.

Epithelioid glioblastomas stratify into established diagnostic subsets upon integrated molecular analysis

“…The current parameters for anaplastic PXA correct diagnosis are prone to manifest in very wide range, and, in turn, some histopathological features resembling PXA could be recognized in other malignant gliomas (1,14,27). Our current findings that many "eGBM" most closely resemble PXA at the epigenetic and cytogenetic levels correspond well with the challenges encountered by neuropathologists in the differential diagnosis between poorly differentiated, highly anaplastic PXA and GBM.…”

“…Moreover, distinct cytogenetic features of this tumor subgroup with an absence of oncogene amplifications, rarity of 10q losses, and frequent CDKN2A deletions (in combination with frequent BRAF mutation) also match PXA better than GBM. The patients' clinical course, with a median overall survival time of nearly 3 years, also favors anaplastic PXA over GBM . Nevertheless, not unexpected due to their high‐grade glioma diagnosis, these tumors exhibited a relatively high recurrence rate.…”

cIMPACT-NOW update 3: recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”

“…However, other types of glioma also harbor CDKN2A/B deletions, but do not have histologic properties, genetic findings or clinical behavior associated with canonical IDH-wildtype glioblastoma. For example, pleomorphic xanthoastrocytomas often harbor a combination of BRAF mutations and CDKN2A/B deletions but are associated with substantially better clinical outcomes than IDH-wildtype glioblastoma [30]. Another subset of IDH-wildtype astrocytic gliomas has recently been delineated as anaplastic astrocytoma with piloid features, characterized by frequent CDKN2A/B deletions and typically accompanied by BRAF pathway gene alterations and ATRX mutation or loss of nuclear expression.…”

BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions are frequent in epithelioid glioblastomas: a histological and molecular analysis focusing on intratumoral heterogeneity

“…Although E-GBM are generally recognized as primary/de novo lesions (9), several E-GBM with a pre-or co-existent lower-grade components have been reported (1,11,18,21,22,24,28,34,35). The fact that most of these lower-grade lesions documented so far were pleomorphic xanthoastrocytomas (PXA) (1,24,34,35) and that both tumors commonly exhibit BRAF V600E supports the possibility that E-GBM and PXA are related; the association was reinforced by a recent study identifying heterozygous deletion of ODZ3 (TEMN3) as a shared genetic alteration, found in 7 of 11 E-GBM and 2 of 5 epithelioid PXA, defined therein as tumors composed predominantly of epithelioid cells with the same features as seen in E-GBM, but also demonstrating at least a small component of classic PXA (1). In addition, a few E-GBM with BRAF V600E have been reported to accompany a low-grade diffuse glioma-like component (11,21,22,28).…”

“…In addition to BRAF V600E as a frequent genetic alteration in PXA, homozygous 9p21.3 deletions involving CDKN2A/B have been identified in 60%-83% of the cases (35,38). Conversely, only a small number of E-GBM has been shown to harbor the homozygous deletions (1,4,28,35), and the frequency in E-GBM is not clear.…”