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首页> 外文期刊>International journal of oncology >TP53 oncomorphic mutations predict resistance to platinum??and taxane?based standard chemotherapy in patients diagnosed with advanced serous ovarian carcinoma
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TP53 oncomorphic mutations predict resistance to platinum??and taxane?based standard chemotherapy in patients diagnosed with advanced serous ovarian carcinoma

机译：TP53的同型突变预测患有晚期浆液性卵巢癌的患者对铂和紫杉烷类标准化疗的耐药性

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Individual mutations in the tumor suppressor TP53 alter p53 protein function. Some mutations create a non?functional protein, whereas others confer oncogenic activity, which we term ‘oncomorphic’. Since mutations in TP53 occur in nearly all ovarian tumors, the objective of this study was to determine the relationship of oncomorphic TP53 mutations with patient outcomes in advanced serous ovarian cancer patients. Clinical and molecular data from 264 high?grade serous ovarian cancer patients uniformly treated with standard platinum??and taxane?based adjuvant chemotherapy were downloaded from The Cancer Genome Atlas?(TCGA) portal. Additionally, patient samples were obtained from the University of Iowa and individual mutations were analyzed in ovarian cancer cell lines. Mutations in the TP53 were annotated and categorized as oncomorphic, loss of function?(LOF), or unclassified. Associations between mutation types, chemoresistance, recurrence, and progression?free survival?(PFS) were calculated. Oncomorphic TP53 mutations were present in 21.3% of ovarian cancers in the TCGA dataset. Patients with oncomorphic TP53 mutations demonstrated significantly worse PFS, a 60% higher risk of recurrence?(HR=1.60, 95% confidence intervals 1.09, 2.33, p=0.015), and higher rates of platinum resistance?(χ2?test p=0.0024) when compared with single nucleotide mutations not categorized as oncomorphic. Furthermore, tumors containing oncomorphic TP53 mutations displayed unique protein expression profiles, and some mutations conferred increased clonogenic capacity in ovarian cancer cell models. Our study reveals that oncomorphic TP53 mutations are associated with worse patient outcome. These data suggest that future studies should take into consideration the functional consequences of TP53 mutations when determining treatment options.
机译：肿瘤抑制因子TP53中的个别突变会改变p53蛋白的功能。一些突变产生一种非功能性蛋白，而另一些则赋予致癌活性，我们称其为“同型”。由于TP53突变几乎发生在所有卵巢肿瘤中，因此本研究的目的是确定癌态性TP53突变与晚期浆液性卵巢癌患者预后的关系。从癌症基因组图谱（TCGA）门户网站下载了264例接受标准铂和紫杉烷类辅助化疗统一治疗的高级别浆液性卵巢癌患者的临床和分子数据。另外，从爱荷华大学获得患者样品，并分析卵巢癌细胞系中的个别突变。 TP53中的突变被注释并归类为同型，功能丧失（LOF）或未分类。计算突变类型，化学耐药性，复发和无进展生存期（PFS）之间的关联。 TCGA数据集中21.3％的卵巢癌中存在同型TP53突变。 TP53突变的患者表现出PFS明显恶化，复发风险高60％（HR = 1.60，95％置信区间1.09，2.33，p = 0.015），铂耐药率更高（χ2检验p = 0.0024）。 ）与未归类为同型的单核苷酸突变比较。此外，含有癌变型TP53突变的肿瘤表现出独特的蛋白质表达谱，并且某些突变赋予卵巢癌细胞模型更高的克隆形成能力。我们的研究表明，同型TP53突变与较差的患者预后相关。这些数据表明，在确定治疗方案时，未来的研究应考虑TP53突变的功能后果。

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