Almost all the current therapies against liver cancer are based on the "one size fits all" principle and offer only limited survival benefit. Fortunately, synthetic lethality (SL) may provide an alternate route towards individualized therapy in liver cancer. The concept that simultaneous losses of two genes are lethal to a cell while a single loss is non-lethal can be utilized to selectively eliminate tumors with genetic aberrations. Methods: To infer liver cancer-specific SL interactions, we propose a computational pipeline termed SiLi (statistical inference-based synthetic lethality identification) that incorporates five inference procedures. Based on large-scale sequencing datasets, SiLi analysis was performed to identify SL interactions in liver cancer. Results: By SiLi analysis, a total of 272 SL pairs were discerned, which included 209 unique target candidates. Among these, polo-like kinase 1 (PLK1) was considered to have considerable therapeutic potential. Further computational and experimental validation of the SL pair TP53-PLK1 demonstrated that inhibition of PLK1 could be a novel therapeutic strategy specifically targeting those patients with TP53-mutant liver tumors. Conclusions: In this study, we report a comprehensive analysis of synthetic lethal interactions of liver cancer. Our findings may open new possibilities for patient-tailored therapeutic interventions in liver cancer.

中文翻译：

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绘制肝癌合成致死相互作用的图谱。

目前几乎所有针对肝癌的疗法都是基于“一刀切”的原则，并且只能提供有限的生存益处。幸运的是，合成致死（SL）可能为肝癌个体化治疗提供另一种途径。两个基因同时丢失对细胞来说是致命的，而单个基因丢失则不致命，这一概念可用于选择性消除具有遗传畸变的肿瘤。方法：为了推断肝癌特异性 SL 相互作用，我们提出了一个名为 SiLi（基于统计推断的合成致死率识别）的计算管道，其中包含五个推断程序。基于大规模测序数据集，进行 SiLi 分析来识别肝癌中的 SL 相互作用。结果：通过SiLi分析，总共识别出272个SL对，其中包括209个独特的候选目标。其中，polo样激酶1（PLK1）被认为具有相当大的治疗潜力。SL 对 TP53-PLK1 的进一步计算和实验验证表明，抑制 PLK1 可能是一种专门针对 TP53 突变肝肿瘤患者的新型治疗策略。结论：在这项研究中，我们报告了肝癌综合致死相互作用的综合分析。我们的研究结果可能为针对患者的肝癌治疗干预措施开辟新的可能性。