ARID1A and TERT promoter mutations in dedifferentiated meningioma
ARID1A and TERT promoter mutations in dedifferentiated meningioma
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DOI：
10.1016/j.cancergen.2015.03.005
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发表时间：
2015-06-01
期刊：
影响因子：
1.9
通讯作者：
Santagata, Sandro
中科院分区：
文献类型：
--
作者：
Abedalthagafi, Malak S.;Bi, Wenya Linda;Santagata, Sandro
与被认为是良性的世界卫生组织(WHO)I级脑膜瘤患者不同，WHO III级脑膜瘤患者的死亡率非常高。脑膜瘤的肿瘤进展机制尚不清楚，但对这些高级别致命性肿瘤患者的有效治疗需要对这些机制有一个详细的了解。我们提出一个脑室内脑膜瘤的病例，最初表现出显著的形态异质性，由独立符合WHO I、II和III级组织病理学标准的不同区域组成。最低级别的区域具有典型的脑膜上皮特征，而最高级别的区域明显去分化。虽然脑膜瘤的进展通常是在放射治疗和系统药物治疗后的复发过程中观察到的，但本病例为我们提供了一个在本土治疗前的背景下组织学进展和肿瘤内异质性的快照。利用全外显子组测序和基于高分辨率阵列的比较基因组杂交，我们观察到不同区域之间显著的遗传异质性。值得注意的是，在较高级别的区域，我们发现非整倍体增加，杂合性逐渐丧失，乳头启动子突变的出现，以及ARID1A的妥协。这些发现为间变性脑膜瘤恶性表型演变中的肿瘤内异质性和恶性进展的潜在途径提供了新的见解。
Unlike patients with World Health Organization (WHO) grade I meningiomas, which are considered benign, patients with WHO grade III meningiomas have very high mortality rates. The principles underlying tumor progression in meningioma are largely unknown, yet a detailed understanding of these mechanisms will be required for effective management of patients with these high grade lethal tumors. We present a case of an intraventricular meningioma that at first presentation displayed remarkable morphologic heterogeneity composed of distinct regions independently fulfilling histopathologic criteria for WHO grade I, II, and III designations. The lowest grade regions had classic meningothelial features, while the highest grade regions were markedly dedifferentiated. Whereas progression in meningiomas is generally observed during recurrence following radiation and systemic medical therapies, the current case offers us a snapshot of histologic progression and intratumoral heterogeneity in a native pretreatment context. Using whole exome sequencing and high resolution array-based comparative genomic hybridization, we observed marked genetic heterogeneity between the various areas. Notably, in the higher grade regions we found increased aneuploidy with progressive loss of heterozygosity, the emergence of mutations in the TEAT promoter, and compromise of ARID1A. These findings provide new insights into intratumoral heterogeneity in the evolution of malignant phenotypes in anaplastic meningiomas and potential pathways of malignant progression.