Identification of causal genetic drivers of human disease through systems-level analysis of regulatory networks.
Identification of causal genetic drivers of human disease through systems-level analysis of regulatory networks.
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DOI：
10.1016/j.cell.2014.09.021
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发表时间：
2014-10-09
期刊：
影响因子：
64.5
通讯作者：
Califano A
中科院分区：
文献类型：
--
作者：
Chen JC;Alvarez MJ;Talos F;Dhruv H;Rieckhof GE;Iyer A;Diefes KL;Aldape K;Berens M;Shen MM;Califano A
人类疾病中驱动突变的识别通常受到队列规模和适当统计模型可用性的限制。我们提出了一个新的框架，系统地发现遗传变异是疾病的因果决定因素，优先考虑基因上游的功能性疾病驱动程序，从实验数据从头推断的监管网络。我们通过鉴定胶质母细胞瘤间充质亚型的遗传决定因素来测试这个框架。我们的分析发现KLHL 9缺失是该亚型的两个先前确定的主调节因子C/EBPβ和C/EBPδ的上游激活因子。拯救KLHL 9表达诱导蛋白酶体降解C/EBP蛋白，废除间充质签名，并降低体外和体内肿瘤活力。在一个独立的队列中，在>50%的间充质病例中证实了KLHL 9的缺失，因此代表了该亚型最常见的遗传决定因素。该方法推广到研究其他人类疾病，包括乳腺癌和阿尔茨海默病。
Identification of driver mutations in human diseases is often limited by cohort size and availability of appropriate statistical models. We propose a novel framework for the systematic discovery of genetic alterations that are causal determinants of disease, by prioritizing genes upstream of functional disease drivers, within regulatory networks inferred de novo from experimental data. We tested this framework by identifying the genetic determinants of the mesenchymal subtype of glioblastoma. Our analysis uncovered KLHL9 deletions as upstream activators of two previously established master regulators of the subtype, C/EBPβ and C/EBPδ. Rescue of KLHL9 expression induced proteasomal degradation of C/EBP proteins, abrogated the mesenchymal signature, and reduced tumor viability in vitro and in vivo. Deletions of KLHL9 were confirmed in >50% of mesenchymal cases in an independent cohort, thus representing the most frequent genetic determinant of the subtype. The method generalized to study other human diseases, including breast cancer and Alzheimer’s disease.
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影响因子：
82.9
作者：
通讯作者：
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影响因子：
50.3
作者：
Phillips, HS;Kharbanda, S;Aldape, K
通讯作者：
Aldape, K
影响因子：
46.9
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Schreiber, Stuart L.;Shamji, Alykhan F.;Clemons, Paul A.;Hon, Cindy;Koehler, Angela N.;Munoz, Benito;Palmer, Michelle;Stern, Andrew M.;Wagner, Bridget K.;Powers, Scott;Lowe, Scott W.;Guo, Xuecui;Krasnitz, Alex;Sawey, Eric T.;Sordella, Raffaella;Stein, Lincoln;Trotman, Lloyd C.;Califano, Andrea;Dalla-Favera, Riccardo;Ferrando, Adolfo;Iavarone, Antonio;Pasqualucci, Laura;Silva, Jose;Stockwell, Brent R.;Hahn, William C.;Chin, Lynda;DePinho, Ronald A.;Boehm, Jesse S.;Gopal, Shuba;Huang, Alan;Root, David E.;Weir, Barbara A.;Gerhard, Daniela S.;Zenklusen, Jean Claude;Roth, Michael G.;White, Michael A.;Minna, John D.;MacMillan, John B.;Posner, Bruce A.
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Posner, Bruce A.
影响因子：
64.8
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通讯作者：
Pasqualucci, Laura
影响因子：
64.5
作者：
Sumazin P;Yang X;Chiu HS;Chung WJ;Iyer A;Llobet-Navas D;Rajbhandari P;Bansal M;Guarnieri P;Silva J;Califano A
通讯作者：
Califano A