Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Acta Neuropathol. 2018 Aug;136(2):273-291. doi: 10.1007/s00401-018-1837-8. Epub 2018 Mar 21.
Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding (t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5 years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.
具有毛细胞型星形细胞瘤（PA）组织学特征，但具有较高的有丝分裂活性和其他高级别特征（特别是微血管增生和栅栏状坏死）的肿瘤通常被指定为间变性毛细胞型星形细胞瘤。这些肿瘤作为一个独立实体的地位尚未得到明确证实，分子特征也只是部分描述。我们对 102 例组织学定义的间变性毛细胞型星形细胞瘤进行了 DNA 甲基化谱分析。对这些 102 例病例与 12 个胶质瘤参考类别中的 158 例参考病例进行 T 分布随机邻域嵌入（t-SNE）和层次聚类分析显示，这些肿瘤中有一个亚组 83 例具有独特的共同 DNA 甲基化谱，与参考类别不同。这些 83 例肿瘤因此被命名为具有毛细胞特征的 DNA 甲基化类间变性星形细胞瘤（MC AAP）。其余 19 例肿瘤分布在参考类别中，大多数病例的进一步检测证实了分子诊断。MC AAP 患者的中位年龄为 41.5 岁。最常见的定位是后颅窝（74%）。CDKN2A/B 缺失（66/83，80%）、MAPK 通路基因改变（49/65，75%，最常影响 NF1，其次是 BRAF 和 FGFR1）和 ATRX 突变或 ATRX 表达缺失（33/74，45%）是最常见的分子改变。所有肿瘤均为 IDH1/2 野生型。MGMT 启动子在 38/83 例肿瘤中甲基化（45%）。预后分析证实与 PA 相比，临床病程较差，但优于 IDH 野生型胶质母细胞瘤。总之，我们表明，一组具有组织学定义的间变性毛细胞型星形细胞瘤形成了一个单独的 DNA 甲基化簇，具有 MAPK 通路基因的反复改变，同时伴有 CDKN2A/B 和 ATRX 的改变，影响的患者平均年龄大于诊断为 PA 的患者，临床预后处于中间水平。
