Zhou Jie, Lai Yiming, Peng Shengmeng, Tang Chen, Chen Yongming, Li Lingfeng, Huang Hai, Guo Zhenghui
Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Front Oncol. 2022 Aug 31;12:957404. doi: 10.3389/fonc.2022.957404. eCollection 2022.
Although TP53 and SPOP are frequently mutated in metastatic prostate cancer (PCa), their prognostic value is ambiguous, and large sample studies are lacking, especially when they co-occur with other genetic alterations.
Genomic data and patients' clinical characteristics in PCa were downloaded from the cBioPortal database. We extensively analyzed other gene alterations in different mutation status of TP53 and SPOP. We further subdivided TP53 and SPOP mutation into subgroups based on different mutation status, and then evaluated the prognostic value. Two classification systems for TP53 survival analysis were used.
A total of 2,172 patients with PCa were analyzed in our study, of which 1,799 were metastatic PCa patients. The mutual exclusivity analysis showed that TP53 and SPOP mutation has a strong mutual exclusion (p<0.001). In multivariable analysis, truncating TP53 mutations (HR=1.773, 95%CI:1.403-2.239, p<0.001) and other TP53 mutations(HR=1.555, 95%CI:1.267-1.908, p<0.001) were independent negative prognostic markers in metastatic PCa, whereas SPOP mutations(HR=0.592, 95%CI:0.427-0.819, p<0.001) were an independent prognostic factor for better prognosis. Mutations in TP53 were significantly associated with wild-type status for SPOP and CDK12, structural variants/fusions for TMPRSS2 and ERG, AR amplification and PTEN deletion (p<0.001). And truncating TP53 mutations have higher AR amplification rates than other TP53 mutations (p=0.022). Consistently, truncating TP53 mutations had a worse prognosis than other TP53 mutations (p<0.05). Then Kaplan-Meier survival curve showed that Co-occurring TP53 mutations in AR amplification or PTEN deletion tumors significantly reduced survival (p<0.05). Furthermore, those with SPOP-mutant tumors with co-occurring TP53 truncating mutations had shorter overall survival than those with SPOP-mutant tumors with wild-type or other TP53 mutations.
This study found that TP53 and SPOP mutations were mutually exclusive and both were independent prognostic markers for metastatic PCa. Genomic alteration and survival analysis revealed that TP53 and SPOP mutations represented distinct molecular subtypes. Our data suggest that molecular stratification on the basis of TP53 and SPOP mutation status should be implemented for metastatic PCa to optimize and modify clinical decision-making.
尽管TP53和SPOP在转移性前列腺癌（PCa）中经常发生突变，但其预后价值尚不明确，且缺乏大样本研究，尤其是当它们与其他基因改变同时出现时。
从cBioPortal数据库下载PCa的基因组数据和患者临床特征。我们广泛分析了TP53和SPOP不同突变状态下的其他基因改变。我们进一步根据不同突变状态将TP53和SPOP突变细分为亚组，然后评估其预后价值。使用了两种TP53生存分析的分类系统。
我们的研究共分析了2172例PCa患者，其中1799例为转移性PCa患者。相互排斥性分析表明，TP53和SPOP突变具有很强的相互排斥性（p<0.001）。在多变量分析中，截短性TP53突变（HR=1.773，95%CI：1.403 - 2.239，p<0.001）和其他TP53突变（HR=1.555，95%CI：1.267 - 1.908，p<0.001）是转移性PCa的独立阴性预后标志物，而SPOP突变（HR=0.592，95%CI：0.427 - 0.819，p<0.001）是预后较好的独立预后因素。TP53突变与SPOP和CDK12的野生型状态、TMPRSS2和ERG的结构变异/融合、AR扩增及PTEN缺失显著相关（p<0.001）。截短性TP53突变的AR扩增率高于其他TP53突变（p=0.022）。同样，截短性TP53突变的预后比其他TP53突变更差（p<0.05）。然后Kaplan-Meier生存曲线显示，AR扩增或PTEN缺失肿瘤中同时存在TP53突变显著降低生存率（p<0.05）。此外，SPOP突变肿瘤同时存在TP53截短突变的患者总生存期比SPOP突变肿瘤具有野生型或其他TP53突变的患者短。
本研究发现TP53和SPOP突变相互排斥，且均为转移性PCa的独立预后标志物。基因组改变和生存分析表明，TP53和SPOP突变代表不同的分子亚型。我们的数据表明，应基于TP53和SPOP突变状态对转移性PCa进行分子分层，以优化和调整临床决策。
