Integrated multi-omics data analyses for exploring the co-occurring and mutually exclusive gene alteration events in colorectal cancer
Integrated multi-omics data analyses for exploring the co-occurring and mutually exclusive gene alteration events in colorectal cancer
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综合多组学数据分析，探索结直肠癌中同时发生和相互排斥的基因改变事件
DOI：
10.1002/humu.24059
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发表时间：
2020-07-05
期刊：
影响因子：
3.9
通讯作者：
Zhang, Dandan
中科院分区：
文献类型：
--
作者：
Zhou, Yuan;Cheng, Xiaoqing;Zhang, Dandan
同时发生和相互排斥的基因改变事件有助于了解致癌作用，但对此类事件的系统筛查非常有限。我们利用癌症基因组图谱 (TCGA) 的跨组学数据进行了成对筛选测试，以识别结直肠癌 (CRC) 中的“命中对”。大量涉及体细胞突变、拷贝数变异和 DNA 甲基化的命中对被发现在 CRC 中非随机发生，例如 KRAS 和 HOXB6、SMAD4 和 PMEPA1。基于这些命中对，我们确定了 32 个合成致死对和 7,527 个与药物反应相关的共现对。我们进一步的生物学实验表明，突变体FCGBP和NUDT12沉默（或突变体TMC3和RPS6KA6沉默）与小干扰RNA的共存降低了细胞活力。此外，新的命中对可能会影响预后。携带IRF5和NEFH、SYNE1和TTN、或MUC16和NEFH同时突变的患者生存结果较差。特别是突变SYNE1和TTNpair的存在不仅影响预后，而且与CRC患者对药物治疗的反应有关。我们的“命中对”基因可能有助于深入了解结直肠癌的发生，并有助于开辟结直肠癌治疗的新途径。
Co-occurring and mutually exclusive gene alteration events are helpful for understanding carcinogenesis but systematic screening for such events is quite limited. We conducted pairwise screening tests to identify "hit pairs" in colorectal cancer (CRC) by utilizing the cross-omics data from The Cancer Genome Atlas (TCGA). Numerous hit pairs involving somatic mutations, copy number variations, and DNA methylation were found to occur nonrandomly in CRC, such asKRASandHOXB6, SMAD4andPMEPA1. Based on these hit pairs, we identified 32 synthetic lethal pairs and 7,527 co-occurring pairs relating to drug response. Our further biological experiments showed that the co-occurrence of mutantFCGBPandNUDT12silencing (or mutantTMC3andRPS6KA6silencing) with small interfering RNA reduced cell viability. Moreover, novel hit pairs could influence prognosis. The patients who carried concurrent mutations ofIRF5andNEFH, SYNE1andTTN, orMUC16andNEFHhad worse survival outcomes. Particularly, the presence of mutantSYNE1andTTNpair not only affects prognosis, but also is related to CRC patients' response to drug treatment. Our "hit pair" genes may provide insights into colorectal carcinogenesis and help open new avenues for CRC therapy.