<b>Comprehensive classification of </b><b><i>TP53</i></b><b> somatic missense variants based on their impact on p53 structural stability</b>

Somatic variation is a major type of genetic variation contributing to human diseases, including cancer. The functional impact of many somatic variants including missense variants remains unclear, hindering the translation of such variation information into clinical applications. We previously developed a protein structural-based method, Ramachandran plot-molecular dynamics simulations (RP-MDS), to predict the function of germline missense variants based on their effects on protein structure stability, which produced successful predictions of the deleterious germline missense variants in multiple cancer-related genes. We reasoned that somatic missense variants and germline missense variants should have similar effects on the stability of the protein structure. In this study, we applied our protein structural-based approach, RP-MDS, to provide a comprehensive classification of the somatic missense variants in <i>TP53</i>. We analyzed 397 somatic missense variants and showed that 195 (49.1%) variants were deleterious due to their disruptions to p53 structure. The results were furthered 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.

体细胞变异（somatic variation）是一类与包括癌症在内的人类疾病相关的主要遗传变异类型。目前，包括错义变异（missense variant）在内的多数体细胞变异的功能影响仍未明确，这阻碍了此类变异信息向临床应用的转化。

我们此前开发了一种基于蛋白质结构的方法——拉马昌德兰绘图-分子动力学模拟（Ramachandran plot-molecular dynamics simulations, RP-MDS），该方法可通过变异对蛋白质结构稳定性的影响预测生殖系错义变异（germline missense variant）的功能，并已在多个癌症相关基因中成功预测出有害的生殖系错义变异。

我们推测，体细胞错义变异与生殖系错义变异对蛋白质结构稳定性的影响机制相近。本研究将该基于蛋白质结构的RP-MDS方法应用于*TP53*基因体细胞错义变异的全面分类分析。我们共分析了397个体细胞错义变异，结果显示其中195个（占比49.1%）变异因破坏p53蛋白结构而具有有害性。该结论进一步通过p53-p21启动子-绿色荧光蛋白（green fluorescent protein, GFP）报告基因实验得到验证。

本研究证实，可通过参考变异对蛋白质结构稳定性的影响来鉴定有害体细胞错义变异。

搜集汇总

背景与挑战

背景概述

该数据集基于RP-MDS方法，对TP53基因的体细胞错义变异进行了全面分类，重点评估这些变异对p53蛋白结构稳定性的影响。研究分析了397个变异，发现其中195个（49.1%）因破坏结构稳定性而有害，并通过p53-p21-GFP报告基因实验验证了结果。数据集发布于2024年，属于癌症基因组学领域，涉及结构生物学和功能预测。