The primacy of NF1 loss as the driver of tumorigenesis in neurofibromatosis type 1-associated plexiform neurofibromas.
The primacy of NF1 loss as the driver of tumorigenesis in neurofibromatosis type 1-associated plexiform neurofibromas.
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1型神经纤维瘤病相关丛状神经纤维瘤中NF1缺失作为肿瘤发生驱动因素的首要地位
DOI：
10.1038/onc.2016.464
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发表时间：
2017-06-01
期刊：
影响因子：
8
通讯作者：
Stewart DR
中科院分区：
文献类型：
--
作者：
Pemov A;Li H;Patidar R;Hansen NF;Sindiri S;Hartley SW;Wei JS;Elkahloun A;Chandrasekharappa SC;NISC Comparative Sequencing Program;Boland JF;Bass S;NCI DCEG Cancer Genomics Research Laboratory;Mullikin JC;Khan J;Widemann BC;Wallace MR;Stewart DR
1 型神经纤维瘤病 (NF1) 是一种常见的肿瘤易感性疾病，由肿瘤抑制基因 NF1 的种系突变引起。 NF1 的一个几乎特异的发现是丛状神经纤维瘤 (PN)，这是一种良性的、可能是先天性的肿瘤，由 NF1 的双等位基因失活引起，PN 可以转化为恶性周围神经鞘瘤，一种侵袭性软组织肉瘤。为了更好地了解非 NF1 遗传对 PN 发病机制的贡献，我们对由具有匹配种系 DNA 的外科 PN 材料建立的 23 个低传代施万细胞培养物进行了全外显子组测序、RNASeq 分析和全基因组拷贝数测定。所有切除的肿瘤均来自常规减瘤手术。当时没有认为肿瘤有恶变的风险；例如，没有疼痛或快速生长。还对肿瘤 DNA 进行了深度 (~500X) NF1 外显子测序。使用 Ampliseq/IonTorrent 平台进行非 NF1 体细胞突变验证。我们鉴定了 100% 的种系 NF1 突变，并发现 74% 的 PN 存在体细胞 NF1 失活。一个具有三个 PN 的个体在每个肿瘤中都有不同的 NF1 体细胞突变。每个样本的体细胞突变（包括 NF1）的中位数为 1（范围 0-8）。 NF1 是唯一在多种肿瘤中反复体细胞失活的基因。全转录组肿瘤 RNA 测序的基因集富集分析确定了与 DNA 复制、端粒维持和延伸、细胞周期进展、信号转导和细胞增殖相关的 5 个显着 (FDR < 0.01) 和 7 个趋势 (0.01 ≤ FDR < 0.02) 基因集。我们发现 PN 中没有复发性非 NF1 位点拷贝数变异。这是第一个针对 NF1 相关 PN 的多样本全外显子组和全转录组测序研究。结合并发拷贝数数据，我们的综合遗传分析揭示了 NF1 缺失作为 PN 肿瘤发生驱动因素的首要作用。
Neurofibromatosis type 1 (NF1) is a common tumor-predisposition disorder due to germline mutations in the tumor suppressor gene NF1 A virtually pathognomonic finding of NF1 is the plexiform neurofibroma (PN), a benign, likely congenital tumor that arises from bi-allelic inactivation of NF1 PN can undergo transformation to a malignant peripheral nerve sheath tumor, an aggressive soft-tissue sarcoma. To better understand the non-NF1 genetic contributions to PN pathogenesis, we performed whole-exome sequencing, RNASeq profiling and genome-wide copy-number determination for 23 low-passage Schwann cell cultures established from surgical PN material with matching germline DNA. All resected tumors were derived from routine debulking surgeries. None of the tumors were considered at risk for malignant transformation at the time;for example, there was no pain or rapid growth. Deep (~500X) NF1 exon sequencing was also conducted on tumor DNA. Non-NF1 somatic mutation verification was performed using the Ampliseq/IonTorrent platform. We identified 100% of the germline NF1 mutations and found somatic NF1 inactivation in 74% of the PN. One individual with three PNs had different NF1 somatic mutations in each tumor. The median number of somatic mutations per sample, including NF1, was one (range 0–8). NF1 was the only gene that was recurrently somatically inactivated in multiple tumors. Gene Set Enrichment Analysis of transcriptome-wide tumor RNA sequencing identified five significant (FDR < 0.01) and seven trending (0.01 ≤ FDR < 0.02) gene sets related to DNA replication, telomere maintenance and elongation, cell cycle progression, signal transduction and cell proliferation. We found no recurrent non-NF1 locus copy-number variation in PN. This is the first multi-sample whole-exome and whole-transcriptome sequencing study of NF1-associated PN. Taken together with concurrent copy-number data, our comprehensive genetic analysis reveals the primacy of NF1 loss as the driver of PN tumorigenesis.
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DOI：
10.1158/1078-0432.ccr-14-3049
发表时间：
2015-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Hirbe AC;Dahiya S;Miller CA;Li T;Fulton RS;Zhang X;McDonald S;DeSchryver K;Duncavage EJ;Walrath J;Reilly KM;Abel HJ;Pekmezci M;Perry A;Ley TJ;Gutmann DH
通讯作者：
Gutmann DH
影响因子：
30.8
作者：
Dodé, C;Levilliers, J;Hardelin, JP
通讯作者：
Hardelin, JP
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
3.8
作者：
Babovic-Vuksanovic, Dusica;Widemann, Brigitte C.;Packer, Roger J.
通讯作者：
Packer, Roger J.
影响因子：
3.9
作者：
Maertens, Ophelia;Brems, Hilde;Messiaen, Ludwine
通讯作者：
Messiaen, Ludwine