Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations
Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations
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DOI：
10.1007/s00401-018-1837-8
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发表时间：
2018-08-01
影响因子：
12.7
通讯作者：
Capper, David
中科院分区：
文献类型：
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作者：
Reinhardt, Annekathrin;Stichel, Damian;Capper, David
具有毛细胞性星形细胞瘤(PA)的组织学特征，但具有核分裂活性增加和附加高级别特征(特别是微血管增殖和栅栏状坏死)的肿瘤通常被称为间变性毛细胞性星形细胞瘤。这些肿瘤作为一个独立实体的地位尚未得到确凿的证明，分子特征也只有部分特征。我们对102例组织学明确的间变性毛细胞星形细胞瘤进行了DNA甲基化分析。对这102例和来自12个胶质瘤参考类别的158个参考病例进行T分布随机邻近嵌入(t-SNE)和系统聚类分析，发现其中83个肿瘤的子集共享与参考类别不同的共同DNA甲基化特征。这83个肿瘤被命名为DNA甲基化类间变性星形细胞瘤(MC AAP)。剩下的19个肿瘤分布在参考类别中，在大多数情况下，额外的测试确认了分子诊断。MC AAP患者的中位年龄为41.5岁。最常见的定位部位是后颅窝(74%)。CDKN2A/B基因缺失(66/83，80%)，MAPK途径基因改变(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。83例肿瘤中有38例(45%)MGMT启动子甲基化。结果分析证实，与PA相比，PA的临床病程较差，但优于IDH野生型胶质母细胞瘤。综上所述，我们发现，组织学上定义的间变性毛细胞性星形细胞瘤的一个亚群形成了一个独立的DNA甲基化簇，MAPK途径基因的反复改变与CDKN2A/B和ATRX的改变相结合，影响到平均年龄比诊断为PA的患者更大的患者，并具有中等的临床结果。
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.