Identification of druggable cancer driver genes amplified across TCGA datasets.
Identification of druggable cancer driver genes amplified across TCGA datasets.
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DOI：
10.1371/journal.pone.0098293
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kouros-Mehr H
中科院分区：
文献类型：
--
作者：
Chen Y;McGee J;Chen X;Doman TN;Gong X;Zhang Y;Hamm N;Ma X;Higgs RE;Bhagwat SV;Buchanan S;Peng SB;Staschke KA;Yadav V;Yue Y;Kouros-Mehr H
癌症基因组图谱（TCGA）项目促进了我们对驱动突变，遗传背景和跨癌症类型激活的关键途径的理解。TCGA数据集的分析主要集中在体细胞突变和易位上，对基因扩增的重视程度较低。在这里，我们描述了一种生物信息学筛选策略，以确定跨TCGA数据集扩增的推定癌症驱动基因。我们对跨越14种癌症亚型的TCGA数据集进行了GISTIC 2分析，并确定了在两个或多个数据集中扩增的461个基因。名单缩小到73个与癌症相关的基因，具有潜在的“药物”特性。大多数基因定位于分布在基因组中的14个扩增子。为了确定潜在的癌症驱动基因，我们分析了个体患者样本的基因拷贝数和mRNA表达数据，并确定了40个与不同致癌过程相关的推定癌症驱动基因。致癌活性通过siRNA/shRNA敲除和通过参考Project Achilles数据集进一步验证。扩增的基因代表了许多基因家族，包括表观遗传调节基因、细胞周期相关基因、DNA损伤反应/修复基因、代谢调节基因以及与Wnt、Notch、Hedgehog、JAK/STAT、NF-κ B和MAPK信号通路相关的基因。在40个推定的驱动基因中，有已知的驱动基因，如EGFR、ERBB 2和PIK 3CA。野生型KRAS在几种癌症类型中扩增，并且KRAS扩增的癌细胞系对KRAS shRNA最敏感，这表明KRAS扩增是独立的致癌事件。许多MAP激酶衔接子与其受体酪氨酸激酶共扩增，例如FGFR衔接子FRS 2和EGFR家族衔接子GRB 7。泛素样连接酶DCUN 1D 1和组蛋白甲基转移酶NSD 3也被鉴定为新的推定的癌症驱动基因。我们讨论了现有的癌症药物靶点的患者定制的影响，我们进一步讨论了药物发现工作的潜在新机会。
The Cancer Genome Atlas (TCGA) projects have advanced our understanding of the driver mutations, genetic backgrounds, and key pathways activated across cancer types. Analysis of TCGA datasets have mostly focused on somatic mutations and translocations, with less emphasis placed on gene amplifications. Here we describe a bioinformatics screening strategy to identify putative cancer driver genes amplified across TCGA datasets. We carried out GISTIC2 analysis of TCGA datasets spanning 14 cancer subtypes and identified 461 genes that were amplified in two or more datasets. The list was narrowed to 73 cancer-associated genes with potential “druggable” properties. The majority of the genes were localized to 14 amplicons spread across the genome. To identify potential cancer driver genes, we analyzed gene copy number and mRNA expression data from individual patient samples and identified 40 putative cancer driver genes linked to diverse oncogenic processes. Oncogenic activity was further validated by siRNA/shRNA knockdown and by referencing the Project Achilles datasets. The amplified genes represented a number of gene families, including epigenetic regulators, cell cycle-associated genes, DNA damage response/repair genes, metabolic regulators, and genes linked to the Wnt, Notch, Hedgehog, JAK/STAT, NF-KB and MAPK signaling pathways. Among the 40 putative driver genes were known driver genes, such as EGFR, ERBB2 and PIK3CA. Wild-type KRAS was amplified in several cancer types, and KRAS-amplified cancer cell lines were most sensitive to KRAS shRNA, suggesting that KRAS amplification was an independent oncogenic event. A number of MAP kinase adapters were co-amplified with their receptor tyrosine kinases, such as the FGFR adapter FRS2 and the EGFR family adapter GRB7. The ubiquitin-like ligase DCUN1D1 and the histone methyltransferase NSD3 were also identified as novel putative cancer driver genes. We discuss the patient tailoring implications for existing cancer drug targets and we further discuss potential novel opportunities for drug discovery efforts.
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影响因子：
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作者：
Herrmann H;Blatt K;Shi J;Gleixner KV;Cerny-Reiterer S;Müllauer L;Vakoc CR;Sperr WR;Horny HP;Bradner JE;Zuber J;Valent P
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影响因子：
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Schuuring, Ed
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8
作者：
Agochiya, M;Brunton, VG;Frame, MC
通讯作者：
Frame, MC
影响因子：
82.9
作者：
Gembarska, Agnieszka;Luciani, Flavie;Fedele, Clare;Russell, Elisabeth A.;Dewaele, Michael;Villar, Stephanie;Zwolinska, Aleksandra;Haupt, Sue;de Lange, Job;Yip, Dana;Goydos, James;Haigh, Jody J.;Haupt, Ygal;Larue, Lionel;Jochemsen, Aart;Shi, Hubing;Moriceau, Gatien;Lo, Roger S.;Ghanem, Ghanem;Shackleton, Mark;Bernal, Federico;Marine, Jean-Christophe
通讯作者：
Marine, Jean-Christophe