Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
Precision Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
Br J Cancer. 2020 Feb;122(3):405-412. doi: 10.1038/s41416-019-0654-8. Epub 2019 Nov 29.
Mutation of TP53 is the most frequent genetic alteration in high-grade serous ovarian cancer (HGSOC). The impact of hotspot mutations of TP53 and protein levels on patient outcomes in HGSOC has not been fully elucidated.
The study population (n = 791) comprised of HGSOC samples with TP53 mutation from TCGA and other publicly available data. Univariate and multivariate cox proportional hazards regression analyses were used to select variables that were correlated with patient survival.
We assessed the effects of TP53 mutations based on type and individual hotspot mutations on patient outcomes in HGSOC. Only hotspot mutations were associated with outcomes. Three hotspot mutations: G266, Y163C, and R282, in aggregate were associated with a worsened overall and recurrence-free survival compared with other hotspot mutations (p < 0.0001 and p = 0.001), other non-hotspot missense mutations (p < 0.0001 and p = 0.008), truncated mutations (p < 0.0001 and p = 0.001), and all other mutations (p < 0.0001 and p = 0.001). Specific hotspot mutations were associated with different protein expression patterns consistent with different functions.
This study provides evidence that individual TP53 hotspot mutations have different impact on HGSOC patient outcomes and potentially TP53 function. Thus the status of particular TP53 aberrations could influence response to therapy and selection of therapeutic agents.
TP53 基因突变是高级别浆液性卵巢癌（HGSOC）中最常见的遗传改变。TP53 热点突变和蛋白水平对 HGSOC 患者结局的影响尚未完全阐明。
研究人群（n=791）包括来自 TCGA 和其他公开可用数据的 HGSOC 样本中 TP53 突变。采用单变量和多变量 cox 比例风险回归分析来选择与患者生存相关的变量。
我们根据 HGSOC 中 TP53 突变的类型和单个热点突变评估了其对患者结局的影响。只有热点突变与结局相关。三个热点突变：G266、Y163C 和 R282，与其他热点突变相比，总体和无复发生存均较差（p<0.0001 和 p=0.001），与其他非热点错义突变（p<0.0001 和 p=0.008）、截短突变（p<0.0001 和 p=0.001）以及所有其他突变（p<0.0001 和 p=0.001）相比。特定的热点突变与不同的蛋白表达模式相关，与不同的功能一致。
本研究提供了证据表明，TP53 单个热点突变对 HGSOC 患者结局有不同的影响，可能对 TP53 功能有不同的影响。因此，特定的 TP53 异常状态可能会影响治疗反应和治疗药物的选择。
