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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Highly aneuploid zebrafish malignant peripheral nerve sheath tumors have genetic alterations similar to human cancers
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Highly aneuploid zebrafish malignant peripheral nerve sheath tumors have genetic alterations similar to human cancers

机译：高度非整倍体斑马鱼恶性周围神经鞘瘤的遗传改变与人类癌症相似

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摘要

Aneuploidy is a hallmark of human cancers, but most mouse cancer models lack the extensive aneuploidy seen in many human tumors. The zebrafish is becoming an increasingly popular model for studying cancer. Here we report that malignant peripheral nerve sheath tumors (MPNSTs) that arise in zebrafish as a result of mutations in either ribosomal protein (rp) genes or in pS3 are highly aneuploid. Karyotyp-ing reveals that these tumors frequently harbor near-triploid numbers of chromosomes, and they vary in chromosome number from cell to cell within a single tumor. Using array comparative genomic hybridization, we found that as in human cancers, certain fish chromosomes are preferentially overrepresented, whereas others are underrepre-sented in many MPNSTs. In addition, we obtained evidence for recurrent subchromosomal amplifications and deletions that may contain genes involved in cancer initiation or progression. These focal amplifications encompassed several genes whose amplification is observed in human tumors, induding met cydinD2. slc4Sa3, and cdk6. One focal amplification induded fgf6a. Increasing fgf signaling via a mutation that overexpresses fgf8 accelerated the onset of MPNSTs in fish bearing a mutation in p53, suggesting that fgf6a itself may be a driver of MPNSTs. Our results suggest that the zebrafish is a useful model in which to study aneuploidy in human cancer and in which to identify candidate genes that may act as drivers in fish and potentially also in human tumors.
机译：非整倍性是人类癌症的标志，但是大多数小鼠癌症模型缺乏在许多人类肿瘤中看到的广泛的非整倍性。斑马鱼正成为研究癌症的一种越来越流行的模型。在这里我们报告说，由于核糖体蛋白（rp）基因或pS3突变而引起的斑马鱼恶性周围神经鞘瘤（MPNSTs）是高度非整倍体。核型分析显示，这些肿瘤经常带有接近三倍体的染色体，并且在单个肿瘤中，不同细胞的染色体数不同。使用阵列比较基因组杂交，我们发现像在人类癌症中一样，某些鱼染色体优先被过度代表，而其他鱼染色体在许多MPNST中被低估。此外，我们获得了可能存在与癌症发生或发展有关的基因的亚染色体复发性扩增和缺失的证据。这些局灶性扩增涵盖了几个基因，这些基因在人肿瘤中被观察到，包括cydinD2。 slc4Sa3和cdk6。一种聚焦扩增包括fgf6a。通过过度表达fgf8的突变增加的fgf信号传导会加速鱼中带有p53突变的MPNSTs的发作，这表明fgf6a本身可能是MPNSTs的驱动力。我们的研究结果表明，斑马鱼是一种有用的模型，可用于研究人类癌症中的非整倍性，并用于识别可能在鱼类以及人类肿瘤中充当驱动因子的候选基因。

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    GuangJun Zhang; Sebastian Hoersch; Adam Amsterdam; Charles A. Whittaker; Jacqueline A. Lees; Nancy Hopkins;

  • 作者单位

    Department of Biology and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;

    Department of Biology and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 Bioinformatics Group, Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany;

    rnDepartment of Biology and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;

    Department of Biology and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;

    Department of Biology and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;

    Department of Biology and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    array cpmparative genomic hybridization; fgf8; met; illumina; copy number alteration;

    机译：阵列比较基因组杂交;fgf8;遇见照亮复制号码变更;

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