Chen James C, Alvarez Mariano J, Talos Flaminia, Dhruv Harshil, Rieckhof Gabrielle E, Iyer Archana, Diefes Kristin L, Aldape Kenneth, Berens Michael, Shen Michael M, Califano Andrea
Department of Systems Biology, Columbia University, 1130 Saint Nicholas Avenue, New York, NY 10032, USA; Center for Computational Biology and Bioinformatics, Columbia University, 1130 Saint Nicholas Avenue, New York, NY 10032, USA; Department of Genetics and Development, Columbia University, 701 West 168th Street, New York, NY 10032, USA.
Department of Systems Biology, Columbia University, 1130 Saint Nicholas Avenue, New York, NY 10032, USA; Center for Computational Biology and Bioinformatics, Columbia University, 1130 Saint Nicholas Avenue, New York, NY 10032, USA.
Cell. 2014 Oct 9;159(2):402-14. doi: 10.1016/j.cell.2014.09.021.
Identification of driver mutations in human diseases is often limited by cohort size and availability of appropriate statistical models. We propose a 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.
人类疾病中驱动突变的识别往往受到队列规模和合适统计模型可用性的限制。我们提出了一个框架，用于系统地发现作为疾病因果决定因素的基因改变，通过在从实验数据中从头推断出的调控网络内，对功能性疾病驱动因子上游的基因进行优先级排序。我们通过识别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KLHL9缺失是该亚型两个先前确定的主要调节因子C/EBPβ和C/EBPδ的上游激活因子。恢复KLHL9表达可诱导C/EBP蛋白的蛋白酶体降解，消除间充质特征，并降低体外和体内肿瘤的活力。在一个独立队列中，超过50%的间充质病例证实了KLHL9缺失，因此它是该亚型最常见的遗传决定因素。该方法可推广用于研究其他人类疾病，包括乳腺癌和阿尔茨海默病。
