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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Highly Parallel Identification Of Essential Genes In Cancer Cells
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Highly Parallel Identification Of Essential Genes In Cancer Cells

机译：癌细胞中基本基因的高度并行鉴定

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More complete knowledge of the molecular mechanisms underlying cancer will improve prevention, diagnosis and treatment. Efforts such as The Cancer Genome Atlas are systematically characterizing the structural basis of cancer, by identifying the genomic mutations associated with each cancer type. A powerful complementary approach is to systematically characterize the functional basis of cancer, by identifying the genes essential for growth and related phenotypes in different cancer cells. Such information would be particularly valuable for identifying potential drug targets. Here, we report the development of an efficient, robust approach to perform genome-scale pooled shRNA screens for both positive and negative selection and its application to systematically identify cell essential genes in 12 cancer cell lines. By integrating these functional data with comprehensive genetic analyses of primary human tumors, we identified known and putative onco-genes such as EGFR, KRAS. MYC. BCR-ABL, MYB, CRKL, and CDK4 that are essential for cancer cell proliferation and also altered in human cancers. We further used this approach to identify genes involved in the response of cancer cells to tumoricidal agents and found 4 genes required for the response of CML cells to imatinib treatment: PTPN1, NF1, SMARCB1, and SMARCE1. and 5 regulators of the response to FAS activation, FAS, FADD, CASP8, ARID1A and CBX1. Broad application of this highly parallel genetic screening strategy will not only facilitate the rapid identification of genes that drive the malignant state and its response to therapeutics but will also enable the discovery of genes that participate in any biological process.
机译：对癌症潜在分子机制的更全面的了解将改善预防，诊断和治疗。诸如癌症基因组图谱之类的工作通过识别与每种癌症类型相关的基因组突变，系统地表征了癌症的结构基础。一种有力的补充方法是，通过鉴定不同癌细胞中生长和相关表型必不可少的基因，系统地表征癌症的功能基础。这样的信息对于识别潜在的药物靶点特别有价值。在这里，我们报告了一种有效，强大的方法的发展，该方法可进行基因组规模的合并的shRNA筛选，以进行阳性和阴性选择，并将其应用于系统地鉴定12种癌细胞系中的细胞必需基因。通过将这些功能数据与人类原发性肿瘤的全面遗传分析相结合，我们确定了已知和推定的癌基因，例如EGFR，KRAS。我的C。 BCR-ABL，MYB，CRKL和CDK4对癌细胞的增殖至关重要，并且在人类癌症中也发生了改变。我们进一步使用这种方法来鉴定参与癌细胞对杀肿瘤剂应答的基因，并发现CML细胞对伊马替尼治疗应答所需的4个基因：PTPN1，NF1，SMARCB1和SMARCE1。和5个负责FAS激活，FAS，FADD，CASP8，ARID1A和CBX1的调节器。这种高度平行的基因筛选策略的广泛应用不仅将有助于快速鉴定驱动恶性状态的基因及其对治疗的反应，还将使发现参与任何生物学过程的基因成为可能。

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