Zhang Wensheng, Dong Yan, Sartor Oliver, Zhang Kun
Bioinformatics Core of Xavier NIH RCMI Center of Cancer Research, Xavier University of Louisiana, New Orleans, LA, USA.
Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA.
Cancer Inform. 2022 Apr 2;21:11769351221087046. doi: 10.1177/11769351221087046. eCollection 2022.
The prevalence of TP53 mutations in advanced prostate cancers (PCa) is 3 to 5 times of the quantity in primary PCa. By an integrative analysis of the Cancer Genome Atlas and Catalogue of Somatic Mutations in Cancer data, we revealed the supporting evidence for 2 complementary hypotheses: - TP53 abnormalities promote metastasis or therapy-resistance of PCa cells, and -part of TP53 mutations in PCa metastases occur after the diagnosis of original cancers. The plausibility of these hypotheses can explain the increased prevalence of TP53 mutations in PCa metastases. With and as the general assumptions, we developed mathematical models to decipher the change of the percentage frequency (prevalence) of TP53 mutations from primary tumors to metastases. The following results were obtained. Compared to TP53-normal patients, TP53-mutated patients had poorer biochemical relapse-free survival, higher Gleason scores, and more advanced t-stages ( < .01). Single-nucleotide variants in metastases more frequently occurred on G bases of the coding sequence than those in primary cancers ( = .03). The profile of TP53 hotspot mutations was significantly different between primary and metastatic PCa as demonstrated in a set of statistical tests ( < .05). By the derived formulae, we estimated that about 40% TP53 mutation records collected from metastases occurred after the diagnosis of the original cancers. Our study provided significant insight into PCa progression. The proposed models can also be applied to decipher the prevalence of mutations on TP53 (or other driver genes) in other cancer types.
晚期前列腺癌（PCa）中TP53突变的发生率是原发性PCa的3至5倍。通过对癌症基因组图谱和癌症体细胞突变目录数据的综合分析，我们揭示了两个互补假设的支持证据：- TP53异常促进PCa细胞的转移或治疗抗性，以及- PCa转移灶中的部分TP53突变发生在原发癌诊断之后。这些假设的合理性可以解释PCa转移灶中TP53突变发生率的增加。以和为一般假设，我们开发了数学模型来解读TP53突变从原发性肿瘤到转移灶的百分比频率（发生率）变化。得到了以下结果。与TP53正常的患者相比，TP53突变的患者生化无复发生存期更差，Gleason评分更高，t分期更晚（<0.01）。转移灶中的单核苷酸变异在编码序列的G碱基上比原发性癌症中更频繁出现（=0.03）。一组统计检验表明，原发性和转移性PCa中TP53热点突变的谱有显著差异（<0.05）。通过推导公式，我们估计从转移灶收集的约40%的TP53突变记录发生在原发癌诊断之后。我们的研究为PCa进展提供了重要见解。所提出的模型也可用于解读其他癌症类型中TP53（或其他驱动基因）突变的发生率。
