Han Yue, Wang Chengyu, Dong Qi, Chen Tingting, Yang Fan, Liu Yaoyao, Chen Bo, Zhao Zhangxiang, Qi Lishuang, Zhao Wenyuan, Liang Haihai, Guo Zheng, Gu Yunyan
Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150086, China.
Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, China.
Mol Ther Nucleic Acids. 2019 Sep 6;17:688-700. doi: 10.1016/j.omtn.2019.07.003. Epub 2019 Jul 17.
Cancer cells generally harbor hundreds of alterations in the cancer genomes and act as crucial factors in the development and progression of cancer. Gene alterations in the cancer genome form genetic interactions, which affect the response of patients to drugs. We developed an algorithm that mines copy number alteration and whole-exome mutation profiles from The Cancer Genome Atlas (TCGA), as well as functional screen data generated to identify potential genetic interactions for specific cancer types. As a result, 4,529 synthetic viability (SV) interactions and 10,637 synthetic lethality (SL) interactions were detected. The pharmacogenomic datasets revealed that SV interactions induced drug resistance in cancer cells and that SL interactions mediated drug sensitivity in cancer cells. Deletions of HDAC1 and DVL1, both of which participate in the Notch signaling pathway, had an SV effect in cancer cells, and deletion of DVL1 induced resistance to HDAC1 inhibitors in cancer cells. In addition, patients with low expression of both HDAC1 and DVL1 had poor prognosis. Finally, by integrating current reported genetic interactions from other studies, the Cancer Genetic Interaction database (CGIdb) (http://www.medsysbio.org/CGIdb) was constructed, providing a convenient retrieval for genetic interactions in cancer.
癌细胞通常在癌症基因组中存在数百种改变，并在癌症的发生和发展中起着关键作用。癌症基因组中的基因改变形成遗传相互作用，影响患者对药物的反应。我们开发了一种算法，可从癌症基因组图谱（TCGA）中挖掘拷贝数改变和全外显子突变谱，以及为识别特定癌症类型的潜在遗传相互作用而生成的功能筛选数据。结果，检测到4529种合成生存能力（SV）相互作用和10637种合成致死性（SL）相互作用。药物基因组学数据集显示，SV相互作用在癌细胞中诱导耐药性，而SL相互作用介导癌细胞中的药物敏感性。参与Notch信号通路的HDAC1和DVL1的缺失在癌细胞中具有SV效应，DVL1的缺失诱导癌细胞对HDAC1抑制剂产生耐药性。此外，HDAC1和DVL1均低表达的患者预后较差。最后，通过整合其他研究中目前报道的遗传相互作用，构建了癌症遗传相互作用数据库（CGIdb）（http://www.medsysbio.org/CGIdb），为癌症中的遗传相互作用提供了便捷的检索。
