The genomic landscape of schwannoma
The genomic landscape of schwannoma
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DOI：
10.1038/ng.3688
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发表时间：
2016-11-01
期刊：
影响因子：
30.8
通讯作者：
Zadeh, Gelareh
中科院分区：
文献类型：
--
作者：
Agnihotri, Sameer;Jalali, Shahrzad;Zadeh, Gelareh
神经鞘瘤是一种常见的周围神经鞘肿瘤，可导致衰弱的发病率。我们进行了综合分析，以确定基因组畸变常见的散发性神经鞘瘤。外显子组序列分析，通过对125个样本进行靶向DNA测序进行验证，除了预期的NF 2破坏外，还发现了ARID 1A、ARID 1B和DDR 1中的复发突变。RNA测序鉴定了12/125例（10%）病例中的复发性读框内SH 3 PXD 2A-HTRA 1融合，基因组分析表明该机制是由染色体10 q上的平衡19-Mb染色体倒位引起的。这种融合与男性性别优势相关，每六名神经鞘瘤患者中就有一名发生这种融合。甲基化分析确定了与解剖位置相关的神经鞘瘤的不同分子亚组。SH 3 PXD 2A-HTRA 1融合蛋白的表达导致磷酸化ERK升高，增殖增加，侵袭和体内肿瘤发生增加。靶向MEK-ERK通路在融合阳性的雪旺细胞中是有效的，这表明了一种可能的治疗方法。
Schwannomas are common peripheral nerve sheath tumors that can cause debilitating morbidities. We performed an integrative analysis to determine genomic aberrations common to sporadic schwannomas. Exome sequence analysis with validation by targeted DNA sequencing of 125 samples uncovered, in addition to expected NF2 disruption, recurrent mutations in ARID1A, ARID1B and DDR1. RNA sequencing identified a recurrent in-frame SH3PXD2A-HTRA1 fusion in 12/125 (10%) cases, and genomic analysis demonstrated the mechanism as resulting from a balanced 19-Mb chromosomal inversion on chromosome 10q. The fusion was associated with male gender predominance, occurring in one out of every six men with schwannoma. Methylation profiling identified distinct molecular subgroups of schwannomas that were associated with anatomical location. Expression of the SH3PXD2A-HTRA1 fusion resulted in elevated phosphorylated ERK, increased proliferation, increased invasion and in vivo tumorigenesis. Targeting of the MEK-ERK pathway was effective in fusion-positive Schwann cells, suggesting a possible therapeutic approach for this subset of tumors.