Tsherniak Aviad, Vazquez Francisca, Montgomery Phil G, Weir Barbara A, Kryukov Gregory, Cowley Glenn S, Gill Stanley, Harrington William F, Pantel Sasha, Krill-Burger John M, Meyers Robin M, Ali Levi, Goodale Amy, Lee Yenarae, Jiang Guozhi, Hsiao Jessica, Gerath William F J, Howell Sara, Merkel Erin, Ghandi Mahmoud, Garraway Levi A, Root David E, Golub Todd R, Boehm Jesse S, Hahn William C
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA, USA.
Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA, USA; Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, USA.
Cell. 2017 Jul 27;170(3):564-576.e16. doi: 10.1016/j.cell.2017.06.010.
Most human epithelial tumors harbor numerous alterations, making it difficult to predict which genes are required for tumor survival. To systematically identify cancer dependencies, we analyzed 501 genome-scale loss-of-function screens performed in diverse human cancer cell lines. We developed DEMETER, an analytical framework that segregates on- from off-target effects of RNAi. 769 genes were differentially required in subsets of these cell lines at a threshold of six SDs from the mean. We found predictive models for 426 dependencies (55%) by nonlinear regression modeling considering 66,646 molecular features. Many dependencies fall into a limited number of classes, and unexpectedly, in 82% of models, the top biomarkers were expression based. We demonstrated the basis behind one such predictive model linking hypermethylation of the UBB ubiquitin gene to a dependency on UBC. Together, these observations provide a foundation for a cancer dependency map that facilitates the prioritization of therapeutic targets.
大多数人类上皮肿瘤存在大量改变，这使得难以预测哪些基因是肿瘤存活所必需的。为了系统地识别癌症依赖性，我们分析了在多种人类癌细胞系中进行的501个全基因组功能丧失筛选。我们开发了DEMETER，这是一个分析框架，可区分RNAi的脱靶效应和靶向效应。在这些细胞系的子集中，有769个基因在与平均值相差六个标准差的阈值下表现出差异需求。通过考虑66,646个分子特征的非线性回归建模，我们找到了426种依赖性（55%）的预测模型。许多依赖性可归为有限的几类，而且出乎意料的是，在82%的模型中，顶级生物标志物是基于表达的。我们展示了一个这样的预测模型背后的基础，该模型将泛素基因UBB的高甲基化与对泛素结合酶UBC的依赖性联系起来。这些观察结果共同为癌症依赖性图谱奠定了基础，有助于确定治疗靶点的优先级。
