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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Systematic investigation of genetic vulnerabilities across cancer cell lines reveals lineage-specific dependencies in ovarian cancer
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Systematic investigation of genetic vulnerabilities across cancer cell lines reveals lineage-specific dependencies in ovarian cancer

机译：对癌细胞系遗传脆弱性的系统研究揭示了卵巢癌的谱系特异性依赖性

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摘要

A comprehensive understanding of the molecular vulnerabilities of every type of cancer will provide a powerful roadmap to guide therapeutic approaches. Efforts such as The Cancer Genome Atlas Project will identify genes with aberrant copy number, sequence, or expression in various cancer types, providing a survey of the genes that may have a causal role in cancer. A complementary approach is to perform systematic loss-of-function studies to identify essential genes in particular cancer cell types. We have begun a systematic effort, termed Project Achilles, aimed at identifying genetic vulnerabilities across large numbers of cancer cell lines. Here, we report the assessment of the essentiality of 11,194 genes in 102 human cancer cell lines. We show that the integration of these functional data with information derived from surveying cancer genomes pinpoints known and previously undescribed lineage-specific dependencies across a wide spectrum of cancers. In particular, we found 54 genes that are specifically essential for the proliferation and viability of ovarian cancer cells and also amplified in primary tumors or differentially overex-pressed in ovarian cancer cell lines. One such gene, PAX8. is focally amplified in 16% of high-grade serous ovarian cancers and expressed at higher levels in ovarian tumors. Suppression of PAX8 selectively induces apoptotic cell death of ovarian cancer cells. These results identify PAX8 as an ovarian lineage-specific dependency. More generally, these observations demonstrate that the integration of genome-scale functional and structural studies provides an efficient path to identify dependencies of specific cancer types on particular genes and pathways.
机译：对每种类型癌症的分子脆弱性的全面理解将为指导治疗方法提供强有力的路线图。诸如癌症基因组图谱项目之类的工作将鉴定在各种癌症类型中拷贝数，序列或表达异常的基因，从而对可能在癌症中起因果关系的基因进行调查。一种补充方法是进行系统的功能丧失研究，以鉴定特定癌细胞类型中的必需基因。我们已经开始了一项名为“阿基里斯计划”（Project Achilles）的系统性工作，旨在确定跨越众多癌细胞系的遗传脆弱性。在这里，我们报告了102个人类癌细胞系中11,194个基因的必要性评估。我们表明，这些功能数据与从调查癌症基因组中获得的信息的整合可以精确地确定各种癌症中已知的和先前未描述的谱系特异性依赖性。特别是，我们发现了54个基因，这些基因对于卵巢癌细胞的增殖和生存特别重要，并且在原发性肿瘤中扩增或在卵巢癌细胞系中差异表达。一种这样的基因，PAX8。在16％的高度浆液性卵巢癌中会被局部放大，并在卵巢肿瘤中高水平表达。 PAX8的抑制选择性诱导卵巢癌细胞的凋亡。这些结果将PAX8鉴定为卵巢谱系特异性依赖性。更普遍地，这些观察结果表明，基因组规模的功能和结构研究的整合提供了一种有效的途径，以鉴定特定癌症类型对特定基因和途径的依赖性。

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    Hiu Wing Cheung; Glenn S. Cowley; Barbara A. Weir; Jesse S. Boehm; Scott Rusin; Justine A. Scott; Alexandra East; Levi D. Ali; Patrick H. Lizotte; Terence C. Wong; Guozhi Jiang; Jessica Hsiao; Craig H. Mermel; Gad Getz; Jordi Barretina; Shuba Gopal; Pablo Tamayo; Joshua Gould; Aviad Tsherniak; Nicolas Stransky; Biao Luo; Yin Ren; Ronny Drapkin; Sangeeta N. Bhatia; Jill P. Mesirov; Levi A. Garraway; Matthew Meyerson; Eric S. Lander; David E. Root; William C. Hahn;

  • 作者单位

    Department of Medical Oncology, Dana-Farber Cancer Institute,Boston, MA 02115,Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Department of Medical Oncology, Dana-Farber Cancer Institute,Boston, MA 02115,Broad Institute of Harvard and MIT, Cambridge, MA 02142,Center for Cancer Genome Discovery, Dana-Farber Cancer Institute,Boston, MA 02115;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Department of Medical Oncology, Dana-Farber Cancer Institute,Boston, MA 02115,Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Harvard-MIT Division of Health Sciences and Technology , Massachusetts Institute of Technology, Cambridge, MA 02139;

    Departments of Pathology, Chevy Chase, MD 20815,Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute,Boston, MA 02115;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142,Harvard-MIT Division of Health Sciences and Technology , Massachusetts Institute of Technology, Cambridge, MA 02139,Departments of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115,Electrical Engineering and Computer Science, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139,Howard Hughes Medical Institute, Chevy Chase, MD 20815;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Department of Medical Oncology, Dana-Farber Cancer Institute,Boston, MA 02115,Broad Institute of Harvard and MIT, Cambridge, MA 02142,Center for Cancer Genome Discovery, Dana-Farber Cancer Institute,Boston, MA 02115 ,Departments of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

    Department of Medical Oncology, Dana-Farber Cancer Institute,Boston, MA 02115,Broad Institute of Harvard and MIT, Cambridge, MA 02142,Center for Cancer Genome Discovery, Dana-Farber Cancer Institute,Boston, MA 02115 , Departments of Pathology, Chevy Chase, MD 20815;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Broad Institute of Harvard and MIT, Cambridge, MA 02142;

    Department of Medical Oncology, Dana-Farber Cancer Institute,Boston, MA 02115,Broad Institute of Harvard and MIT, Cambridge, MA 02142,Center for Cancer Genome Discovery, Dana-Farber Cancer Institute,Boston, MA 02115 ,Departments of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

  • 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

    high throughput; rnai; oncogene; lineage;

    机译：高通量;RNAi;致癌基因;谱系;

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