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 as KRAS and HOXB6, SMAD4 and PMEPA1. 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 mutant FCGBP and NUDT12 silencing (or mutant TMC3 and RPS6KA6 silencing) with small interfering RNA reduced cell viability. Moreover, novel hit pairs could influence prognosis. The patients who carried concurrent mutations of IRF5 and NEFH, SYNE1 and TTN, or MUC16 and NEFH had worse survival outcomes. Particularly, the presence of mutant SYNE1 and TTN pair 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.

中文翻译：

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综合多组学数据分析，用于探索结直肠癌中同时发生和相互排斥的基因改变事件。

共同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。我们利用来自癌症基因组图谱 (TCGA) 的交叉组学数据进行了成对筛查测试，以识别结直肠癌 (CRC) 中的“命中对”。发现许多涉及体细胞突变、拷贝数变异和 DNA 甲基化的命中对在 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，突变的FCGBP和NUDT12用小干扰 RNA沉默（或突变TMC3和RPS6KA6沉默）降低细胞活力。此外，新的命中对可能会影响预后。谁进行的并发突变的患者IRF5和NEFH，SYNE1和TTN，或MUC16和NEFH有更糟糕的生存结果。特别是突变SYNE1和TTN对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”基因可能会提供对结直肠癌发生的见解，并有助于为 CRC 治疗开辟新的途径。