体细胞变异是导致包括癌症在内的人类疾病的主要遗传变异类型。在已鉴定的大量体细胞变异中，许多体细胞变异，特别是错义变异的功能影响仍不清楚。功能信息的缺乏阻碍了将丰富的变异数据转化为临床应用。我们之前开发了一种名为 Ramachandran 图分子动力学模拟 (RP-MDS) 的方法，旨在根据种系错义变异对蛋白质结构稳定性的影响来预测其功能，并成功应用于预测多种未分类种系错义变异的有害性。癌症基因。我们假设，无论其遗传起源如何，体细胞错义变异和种系错义变异可能对其受影响的蛋白质结构的稳定性产生类似的影响。因此，为种系错义变异设计的 RP-MDS 方法也应适用于预测体细胞错义变异的功能。在当前的研究中，我们使用 TP53 中的体细胞错义变异作为模型来检验我们的假设。在分析的 397 个体细胞错义变异中，RP-MDS 预测有 195 个 (49.1%) 变异是有害的，因为它们显着扰乱了 p53 结构。通过使用 p53-p21 启动子-绿色荧光蛋白 (GFP) 报告基因检测，结果在很大程度上得到了验证。我们的研究表明，可以通过参考其对蛋白质结构稳定性的影响来识别有害的体细胞错义变异。© 作者 2024。由牛津大学出版社出版。

Somatic variation is a major type of genetic variation contributing to human diseases including cancer. Of the vast quantities of somatic variants identified, the functional impact of many somatic variants, in particular the missense variants, remains unclear. Lack of the functional information prevents the translation of rich variation data into clinical applications. We previously developed a method named Ramachandran Plot-Molecular Dynamics Simulations (RP-MDS), aiming to predict the function of germline missense variants based on their effects on protein structure stability, and successfully applied to predict the deleteriousness of unclassified germline missense variants in multiple cancer genes. We hypothesized that regardless of their different genetic origins, somatic missense variants and germline missense variants could have similar effects on the stability of their affected protein structure. As such, the RP-MDS method designed for germline missense variants should also be applicable to predict the function of somatic missense variants. In the current study, we tested our hypothesis by using the somatic missense variants in TP53 as a model. Of the 397 somatic missense variants analyzed, RP-MDS predicted that 195 (49.1%) variants were deleterious as they significantly disturbed p53 structure. The results were largely validated by using a p53-p21 promoter-green fluorescent protein (GFP) reporter gene assay. Our study demonstrated that deleterious somatic missense variants can be identified by referring to their effects on protein structural stability.© The Author(s) 2024. Published by Oxford University Press.