4.6 Article

Pleomorphic xanthoastrocytoma is a heterogeneous entity with pTERT mutations prognosticating shorter survival

Journal

ACTA NEUROPATHOLOGICA COMMUNICATIONS
Volume 10, Issue 1, Pages -

Publisher

BMC
DOI: 10.1186/s40478-021-01308-1

Keywords

Pleomorphic xanthoastrocytoma; Ganglioglioma; Epithelioid glioblastoma; BRAF V600E; pTERT mutation; DNA methylation array profiling

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Funding

  1. Projekt DEAL

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In this study, we compared the morphological and DNA methylation characteristics of pleomorphic xanthoastrocytoma (PXA) and found that PXA is more histologically diverse than previously assumed. DNA methylation analysis can assist in differentiating PXA from other tumor types with similar morphology. We also discovered that canonical pTERT mutations are associated with poor prognosis in PXA.
Pleomorphic xanthoastrocytoma (PXA) in its classic manifestation exhibits distinct morphological features and is assigned to CNS WHO grade 2 or grade 3. Distinction from glioblastoma variants and lower grade glial and glioneuronal tumors is a common diagnostic challenge. We compared a morphologically defined set of PXA (histPXA) with an independent set, defined by DNA methylation analysis (mcPXA). HistPXA encompassed 144 tumors all subjected to DNA methylation array analysis. Sixty-two histPXA matched to the methylation class mcPXA. These were combined with the cases that showed the mcPXA signature but had received a histopathological diagnosis other than PXA. This cohort constituted a set of 220 mcPXA. Molecular and clinical parameters were analyzed in these groups. Morphological parameters were analyzed in a subset of tumors with FFPE tissue available. HistPXA revealed considerable heterogeneity in regard to methylation classes, with methylation classes glioblastoma and ganglioglioma being the most frequent mismatches. Similarly, the mcPXA cohort contained tumors of diverse histological diagnoses, with glioblastoma constituting the most frequent mismatch. Subsequent analyses demonstrated the presence of canonical pTERT mutations to be associated with unfavorable prognosis among mcPXA. Based on these data, we consider the tumor type PXA to be histologically more varied than previously assumed. Histological approach to diagnosis will predominantly identify cases with the established archetypical morphology. DNA methylation analysis includes additional tumors in the tumor class PXA that share similar DNA methylation profile but lack the typical morphology of a PXA. DNA methylation analysis also assist in separating other tumor types with morphologic overlap to PXA. Our data suggest the presence of canonical pTERT mutations as a robust indicator for poor prognosis in methylation class PXA.

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