The genetic landscape
of anaplastic pleomorphic xanthoastrocytoma
First published: 27 July 2018
This article has been
accepted for publication and undergone full peer review but has not been
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Please cite this article as doi: 10.1111/bpa.12639
Abstract
Pleomorphic xanthoastrocytoma
(PXA) is an astrocytic neoplasm that is typically well circumscribed and can
have a relatively favorable prognosis. Tumor progression to anaplastic PXA (WHO
grade III), however, is associated with a more aggressive biologic behavior and
worse prognosis. The factors that drive anaplastic progression are largely
unknown. We performed comprehensive genomic profiling on a set of twenty‐three PXAs from 19 patients,
including 15 with anaplastic PXA. Four patients had tumor tissue from multiple
recurrences, including two with anaplastic progression. We find that PXAs are
genetically defined by the combination of CDKN2A biallelic
inactivation and RAFalterations that were present in all 19 cases,
most commonly as CDKN2A homozygous deletion and BRAF p.V600E
mutation but also occasionally BRAF or RAF1 fusions
or other rearrangements. The third most commonly altered gene in anaplastic PXA
was TERT, with 47% (7/15) harboring TERT alterations,
either gene amplification (n=2) or promoter hotspot mutation (n=5). In tumor
pairs analyzed before and after anaplastic progression, two had increased copy
number alterations and one had TERT promoter mutation at
recurrence. Less commonly altered genes included TP53, BCOR, BCORL1, ARID1A, ATRX,PTEN,
and BCL6. All PXA in this cohort were IDH and histone H3 wildtype,
and did not contain alterations in EGFR. Genetic profiling
performed on six regions from the same tumor identified intratumoral genomic
heterogeneity, likely reflecting clonal evolution during tumor progression.
Overall, anaplastic PXA is characterized by the combination of CDKN2A biallelic
inactivation and oncogenic RAF kinase signaling as well as a relatively small
number of additional genetic alterations, with the most common https://doi.org/10.1111/bpa.12639
