Department of Neurological Surgery, University of California San Francisco, San Francisco, CA.
Division of Neuropathology, Department of Pathology, University of California San Francisco, San Francisco, CA.
Brain Pathol. 2019 Jan;29(1):85-96. doi: 10.1111/bpa.12639. Epub 2018 Nov 6.
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 23 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 RAF alterations 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 being TERT amplification or promoter mutation. These data define a distinct molecular profile for PXA and suggest additional genetic alterations, including TERT, may be associated with anaplastic progression.
多形性黄色星形细胞瘤（PXA）是一种星形细胞瘤，通常界限清楚，预后相对较好。然而，肿瘤向间变性 PXA（WHO 分级 III）进展与更具侵袭性的生物学行为和更差的预后相关。导致间变性进展的因素在很大程度上尚不清楚。我们对 19 名患者的 23 例 PXA 进行了全面的基因组分析，其中包括 15 例间变性 PXA。4 名患者有多次复发的肿瘤组织，其中 2 例有间变性进展。我们发现 PXA 是由 CDKN2A 双等位基因失活和 RAF 改变共同定义的，这在所有 19 例中均存在，最常见的是 CDKN2A 纯合缺失和 BRAF p.V600E 突变，但偶尔也会出现 BRAF 或 RAF1 融合或其他重排。在间变性 PXA 中第三常见改变的基因是 TERT，有 47%（15/32）存在 TERT 改变，要么是基因扩增（n=2），要么是启动子热点突变（n=5）。在分析间变性进展前后的肿瘤对中，有两个肿瘤的拷贝数改变增加，一个肿瘤在复发时存在 TERT 启动子突变。改变较少的基因包括 TP53、BCOR、BCORL1、ARID1A、ATRX、PTEN 和 BCL6。本队列中的所有 PXA 均为 IDH 和组蛋白 H3 野生型，不含有 EGFR 改变。对同一肿瘤的六个区域进行的基因谱分析确定了肿瘤内的基因组异质性，可能反映了肿瘤进展过程中的克隆进化。总体而言，间变性 PXA 的特征是 CDKN2A 双等位基因失活和致癌 RAF 激酶信号以及相对较少的其他遗传改变，最常见的是 TERT 扩增或启动子突变。这些数据为 PXA 定义了一个独特的分子谱，并提示其他遗传改变，包括 TERT，可能与间变性进展有关。
