First insight into the somatic mutation burden of neurofibromatosis type 2-associated grade I and grade II meningiomas: a case report comprehensive genomic study of two cranial meningiomas with vastly different clinical presentation.
First insight into the somatic mutation burden of neurofibromatosis type 2-associated grade I and grade II meningiomas: a case report comprehensive genomic study of two cranial meningiomas with vastly different clinical presentation.
复制标题
DOI：
10.1186/s12885-017-3127-6
复制
发表时间：
2017-02-13
期刊：
影响因子：
3.8
通讯作者：
Germanwala AV
中科院分区：
文献类型：
--
作者：
Dewan R;Pemov A;Dutra AS;Pak ED;Edwards NA;Ray-Chaudhury A;Hansen NF;Chandrasekharappa SC;Mullikin JC;Asthagiri AR;NISC Comparative Sequencing Program;Heiss JD;Stewart DR;Germanwala AV
神经纤维瘤病2(NF2)是一种罕见的常染色体显性遗传性神经系统肿瘤易感性疾病，由NF2的两个拷贝之一的结构性失活引起。脑膜瘤影响了大约一半的NF2患者，并与更高的疾病负担有关。目前，NF2相关脑膜瘤的体细胞突变情况在很大程度上仍未得到研究。在这里，我们提出了一项对良性脑膜瘤和非典型脑膜瘤的深入基因组研究，这两种脑膜瘤都来自一名NF2患者。虽然I级肿瘤没有症状，但II级肿瘤表现出异常高的生长速度：在一年内扩大到初始体积的335倍。用全外显子组测序(WES)结合光谱核型分析(SKY)和SNP阵列拷贝数分析对两种肿瘤的基因组进行检测。为了更好地了解非典型脑膜瘤的克隆性成分，将肿瘤分为四个部分，每个部分都进行了独立的研究。这两种肿瘤都有NF2的第二次拷贝失活，证实了该基因在脑膜瘤形成中的中心作用。良性肿瘤的基因组与正常二倍体细胞非常相似，只有一个有害突变(EPHB3)。相比之下，II级肿瘤的染色体结构高度重排，但在所有分析的片段中是一致的，这意味着这个巨大而快速生长的肿瘤由相对较少的克隆组成。除了多次得失外，II级脑膜瘤还存在大量的染色体易位。对非典型肿瘤的WES分析在所有片段中发现了两个基因：ADAMTSL3和CAPN5的有害突变，表明这些突变存在于经历快速克隆性扩张的细胞中。这是第一次对NF2相关脑膜瘤进行WES研究。除了第二次NF2拷贝失活，我们发现两种肿瘤的躯体负担都很低，而在非典型脑膜瘤中基因组的不稳定性水平很高。基因组的不稳定性导致基因剂量的改变和多基因结构完整性的损害可能是II级肿瘤高生长率的主要原因。进一步研究ADAMTSL3和CAPN5可能有助于阐明它们在脑膜瘤发病机制中的分子意义。本文的在线版本(doi：10.1186/s12885-0173127-6)包含补充材料，授权用户可以使用。
Neurofibromatosis type 2 (NF2) is a rare autosomal dominant nervous system tumor predisposition disorder caused by constitutive inactivation of one of the two copies of NF2. Meningiomas affect about one half of NF2 patients, and are associated with a higher disease burden. Currently, the somatic mutation landscape in NF2-associated meningiomas remains largely unexamined. Here, we present an in-depth genomic study of benign and atypical meningiomas, both from a single NF2 patient. While the grade I tumor was asymptomatic, the grade II tumor exhibited an unusually high growth rate: expanding to 335 times its initial volume within one year. The genomes of both tumors were examined by whole-exome sequencing (WES) complemented with spectral karyotyping (SKY) and SNP-array copy-number analyses. To better understand the clonal composition of the atypical meningioma, the tumor was divided in four sections and each section was investigated independently. Both tumors had second copy inactivation of NF2, confirming the central role of the gene in meningioma formation. The genome of the benign tumor closely resembled that of a normal diploid cell and had only one other deleterious mutation (EPHB3). In contrast, the chromosomal architecture of the grade II tumor was highly re-arranged, yet uniform among all analyzed fragments, implying that this large and fast growing tumor was composed of relatively few clones. Besides multiple gains and losses, the grade II meningioma harbored numerous chromosomal translocations. WES analysis of the atypical tumor identified deleterious mutations in two genes: ADAMTSL3 and CAPN5 in all fragments, indicating that the mutations were present in the cell undergoing fast clonal expansion This is the first WES study of NF2-associated meningiomas. Besides second NF2 copy inactivation, we found low somatic burden in both tumors and high level of genomic instability in the atypical meningioma. Genomic instability resulting in altered gene dosage and compromised structural integrity of multiple genes may be the primary reason of the high growth rate for the grade II tumor. Further study of ADAMTSL3 and CAPN5 may lead to elucidation of their molecular implications in meningioma pathogenesis. The online version of this article (doi:10.1186/s12885-017-3127-6) contains supplementary material, which is available to authorized users.