Whole Exome Sequencing Reveals the Order of Genetic Changes during Malignant Transformation and Metastasis in a Single Patient with NF1-plexiform Neurofibroma.
Whole Exome Sequencing Reveals the Order of Genetic Changes during Malignant Transformation and Metastasis in a Single Patient with NF1-plexiform Neurofibroma.
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DOI：
10.1158/1078-0432.ccr-14-3049
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发表时间：
2015-09-15
期刊：
影响因子：
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通讯作者：
Gutmann DH
中科院分区：
文献类型：
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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
恶性周围神经鞘肿瘤（MPNSTs）在1型神经纤维瘤病（NF1）患者中发生的频率增加，它们可能起源于良性丛状神经纤维瘤的前体。虽然先前的研究采用了多种发现方法来发现与MPNST发病机制相关的基因，但目前尚不清楚哪些分子事件与丛状神经纤维瘤的MPNST进化相关。对网状神经纤维瘤（n=3）、MPNST和来自单个NF1患者14年转移的活检材料进行全外显子组测序。其他验证案例用于评估参与恶性进展的候选基因，而小鼠MPNST模型用于功能分析。随着肿瘤从良性向恶性发展，体细胞NF1基因突变的细胞比例增加，表明MPNST的发展是一个克隆过程。在原发肿瘤和转移性病变中发现了拷贝数变异，包括TP53基因的一个拷贝丢失，但在良性前驱性病变中没有发现。发现了数量有限的非同义体细胞突变基因（βIII-spectrin和ZNF208），其中一些基因在其他原发和转移性MPNST样本中得到了验证。最后，在大多数MPNST中观察到βIII-spectrin表达增加，shrna介导的敲低降低了小鼠MPNST在体内的生长。总的来说，追踪单个NF1患者MPNST分子进化的能力，为未来的机制研究提供了对疾病发病机制和进展重要的遗传事件序列的新见解。
Malignant peripheral nerve sheath tumors (MPNSTs) occur at increased frequency in individuals with neurofibromatosis type 1 (NF1), where they likely arise from benign plexiform neurofibroma precursors. While previous studies have employed a variety of discovery approaches to discover genes associated with MPNST pathogenesis, it is currently unclear what molecular events are associated with the evolution of MPNST from plexiform neurofibroma. Whole exome sequencing was performed on biopsy materials representing plexiform neurofibroma (n=3), MPNST, and metastasis from a single individual with NF1 over a 14-year period. Additional validation cases were used to assess candidate genes involved in malignant progression, while a murine MPNST model was employed for functional analysis. There was an increasing proportion of cells with a somatic NF1 gene mutation as the tumors progressed from benign to malignant, suggesting a clonal process in MPNST development. Copy number variations, including loss of one copy of the TP53 gene, were identified in the primary tumor and the metastatic lesion, but not in benign precursor lesions. A limited number of genes with non-synonymous somatic mutations (βIII-spectrin and ZNF208) were discovered, several of which were validated in additional primary and metastatic MPNST samples. Lastly, increased βIII-spectrin expression was observed in the majority of MPNSTs, and shRNA-mediated knockdown reduced murine MPNST growth in vivo. Collectively, the ability to track the molecular evolution of MPNST in a single individual with NF1 offers new insights into the sequence of genetic events important for disease pathogenesis and progression for future mechanistic study.