Once called “silent mutations” and assumed to have no effect on protein structure and function, synonymous variants are now recognized to be drivers for some cancers. There have been significant advances in our understanding of the numerous mechanisms by which synonymous single nucleotide variants (sSNVs) can affect protein structure and function by affecting pre-mRNA splicing, mRNA expression, stability, folding, miRNA binding, translation kinetics, and co-translational folding. This review highlights the need for considering sSNVs in cancer biology to gain a better understanding of the genetic determinants of human cancers and to improve their diagnosis and treatment. We surveyed the literature for reports of sSNVs in cancer and found numerous studies on the consequences of sSNVs on gene function with supporting in vitro evidence. We also found reports of sSNVs that have statistically significant associations with specific cancer types but for which in vitro studies are lacking to support the reported associations. Additionally, we found reports of germline and somatic sSNVs that were observed in numerous clinical studies and for which in silico analysis predicts possible effects on gene function. We provide a review of these investigations and discuss necessary future studies to elucidate the mechanisms by which sSNVs disrupt protein function and are play a role in tumorigeneses, cancer progression, and treatment efficacy. As splicing dysregulation is one of the most well recognized mechanisms by which sSNVs impact protein function, we also include our own in silico analysis for predicting which sSNVs may disrupt pre-mRNA splicing.

中文翻译：

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同义变异：我们理解癌症驱动因素和治疗结果的必要细微差别

曾经被称为“沉默突变”并被认为对蛋白质结构和功能没有影响的同义变异现在被认为是某些癌症的驱动因素。我们对同义单核苷酸变异 (sSNV) 通过影响前体 mRNA 剪接、mRNA 表达、稳定性、折叠、miRNA 结合、翻译动力学和协同作用影响蛋白质结构和功能的众多机制的理解取得了重大进展。平移折叠。这篇综述强调了在癌症生物学中考虑 sSNV 的必要性，以更好地了解人类癌症的遗传决定因素并改进其诊断和治疗。我们调查了有关癌症中 sSNV 报告的文献，并发现了大量关于 sSNV 对基因功能影响的研究，并提供了体外证据支持。我们还发现了 sSNV 的报告，这些报告与特定癌症类型具有统计学上显着的关联，但缺乏体外研究来支持所报告的关联。此外，我们发现了在许多临床研究中观察到的种系和体细胞 sSNV 的报告，并且计算机分析预测了它们对基因功能的可能影响。我们对这些研究进行了回顾，并讨论了必要的未来研究，以阐明 sSNV 破坏蛋白质功能并在肿瘤发生、癌症进展和治疗效果中发挥作用的机制。由于剪接失调是 sSNV 影响蛋白质功能的最广为人知的机制之一，我们还包括我们自己的计算机分析，以预测哪些 sSNV 可能会破坏 pre-mRNA 剪接。