BACKGROUND Next-generation sequencing (NGS) has been advancing the progress of detection of disease-associated genetic variants and genome-wide profiling of expressed sequences over the past decade. NGS enables the analyses of multiple regions of a genome in a single reaction format and has been shown to be a cost-effective and efficient tool for root-cause analysis of disease and optimization of treatment. NGS has been leading global efforts to device personalized and precision medicine (PM) in clinical practice. The effectiveness of NGS for the aforementioned applications has been proven unequivocal for multifactorial diseases like cancer. However, definitive prediction of cancer markers for all types of diseases and for global populations still remains highly rewarding because of the diversity of cancer types and genetic variants in human. RESULTS We performed exome sequencing of four samples in quest of critical genetic factor/s associated with liver cancer. By imposing knowledge-based filter chains, we have revealed a panel of genetic variants, which are unrecognized by current major genomics data repositories. Total 20 MNV-induced, 5 INDEL-induced, and 31 SNV-induced neoplasm-exclusive genes were revealed through NGS data acquisition followed by data curing with the application of quality filter chains. Liver-specific expression profile of the identified gene pool is directed to the selection of 17 genes which could be the as likely causative genetic factors for liver cancer. Further study on expression level and relevant functional significance enables us to identify and conclude the following four novel variants, viz., c.416T>C (p.Phe139Ser) in SORD, c.1048_1049delGCinsCG (p.Ala350Arg) in KRT6A, c.1159G>T (p.Gly387Cys) in SVEP1, and c.430G>C (p.Gly144Arg) in MRPL38 as a critical genetic factor for liver cancer. CONCLUSION By applying a novel data prioritizing rationale, we explored a panel of previously unaddressed liver cancer-associated variants. These findings may have an opportunity for early prediction of neoplasm/cancer in liver and designing of relevant personalized/precision liver cancer therapeutics in clinical practice. Since NGS protocol is associated with tons of non-specific mutations due to the variation in background genetic makeup of subjects, therefore, our method of data curing could be applicable for more effective screening of global genetic variants related to disease onset, progression, and remission.

中文翻译：

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一种新颖的知识数据增强方法揭示了与肝癌相关的独特遗传变异。

背景技术在过去的十年中，下一代测序（NGS）一直在促进疾病相关遗传变异的检测和表达序列的全基因组分析。NGS能够以单一反应形式分析基因组的多个区域，并且已被证明是一种用于疾病根本原因分析和治疗优化的经济高效的工具。NGS一直在领导全球在临床实践中使用个性化和精确医学（PM）设备的努力。NGS对于上述应用的有效性已被证明对于癌症等多因素疾病而言是明确的。然而，由于人类癌症类型和遗传变异的多样性，对所有类型疾病和全球人群的癌症标志物的明确预测仍然具有很高的回报。结果我们对四个样本进行了外显子组测序，以寻求与肝癌相关的关键遗传因素。通过强加基于知识的过滤链，我们揭示了一组遗传变异，这些变异目前未被主要的基因组学数据库所认可。通过NGS数据采集揭示了总共20个MNV诱导的，5个INDEL诱导的和31个SNV诱导的肿瘤排他性基因，然后通过应用优质过滤链进行数据固化。已鉴定基因库的肝脏特异性表达谱涉及选择17个基因，这些基因可能是肝癌的可能致病遗传因素。对表达水平和相关功能意义的进一步研究使我们能够鉴定和推断以下四个新的变体，即SORD中的c.416T> C（p.Phe139Ser）。KRT6A中的1048_1049delGCinsCG（p.Ala350Arg），SVEP1中的c.1159G> T（p.Gly387Cys）和MRPL38中的c.430G> C（p.Gly144Arg）是肝癌的关键遗传因子。结论通过应用新颖的数据对基本原理进行优先排序，我们探索了一组先前未解决的肝癌相关变体。这些发现可能为早期预测肝脏肿瘤/癌症以及设计临床实践中相关的个性化/精确肝癌治疗药物提供机会。由于由于受试者背景遗传组成的变化，NGS方案与大量非特异性突变相关，因此，我们的数据治疗方法可适用于更有效地筛查与疾病发作，进展和缓解相关的全球遗传变异。MRPL38中的430G> C（p.Gly144Arg）是肝癌的关键遗传因子。结论通过应用新颖的数据对基本原理进行优先排序，我们探索了一组先前未解决的肝癌相关变体。这些发现可能为早期预测肝脏肿瘤/癌症以及设计临床实践中相关的个性化/精确肝癌治疗药物提供机会。由于NGS方案由于受试者背景遗传组成的变化而与大量非特异性突变相关联，因此，我们的数据治疗方法可适用于更有效地筛查与疾病发作，进展和缓解相关的全球遗传变异。MRPL38中的430G> C（p.Gly144Arg）是肝癌的关键遗传因子。结论通过应用新颖的数据对基本原理进行优先排序，我们探索了一组先前未解决的肝癌相关变体。这些发现可能为早期预测肝脏肿瘤/癌症以及设计临床实践中相关的个性化/精确肝癌治疗药物提供机会。由于由于受试者背景遗传组成的变化，NGS方案与大量非特异性突变相关，因此，我们的数据治疗方法可适用于更有效地筛查与疾病发作，进展和缓解相关的全球遗传变异。我们探索了一组先前未解决的肝癌相关变体。这些发现可能为早期预测肝脏肿瘤/癌症以及设计临床实践中相关的个性化/精确肝癌治疗药物提供机会。由于由于受试者背景遗传组成的变化，NGS方案与大量非特异性突变相关，因此，我们的数据治疗方法可适用于更有效地筛查与疾病发作，进展和缓解相关的全球遗传变异。我们探索了一组先前未解决的肝癌相关变体。这些发现可能为早期预测肝脏肿瘤/癌症以及设计临床实践中相关的个性化/精确肝癌治疗药物提供机会。由于由于受试者背景遗传组成的变化，NGS方案与大量非特异性突变相关，因此，我们的数据治疗方法可适用于更有效地筛查与疾病发作，进展和缓解相关的全球遗传变异。