Department of Urology, Qilu Hospital of Shandong University, Ji'nan, 250012, PR China.
Key Laboratory of Urinary Precision Diagnosis and Treatment in Universities of Shandong, Ji'nan, 250012, PR China.
Prostate Cancer Prostatic Dis. 2021 Jun;24(2):482-491. doi: 10.1038/s41391-020-00302-3. Epub 2020 Nov 19.
Prostate cancer (PCa) shows racial disparity in clinical and genomic characteristics, and Asian patients with PCa often present with more aggressive phenotypes at diagnosis. The ability of TP53 to serve as a prognostic biomarker of PCa has been well studied in Western populations. However, no studies to date have examined the role of TP53 in the disparities of primary hormone-naïve prostate cancer (HNPC) between Chinese and Western populations.
We collected prostate tumors and matched normal tissues or blood samples to perform targeted next-generation sequencing of 94 Chinese primary localized HNPC samples, and correlated these genomic profiles with clinical outcomes. The OncoKB knowledge database was used to identify and classify actionable alterations.
The aberrations of PTEN, CDK12, and SPOP in Chinese HNPC samples were similar to those in the Western samples. However, we demonstrated an association of a high frequency of TP53 alterations (21/94) with a relatively higher percentage of alterations in the Wnt signaling pathway (15/94) in Chinese HNPC. Additionally, we highlighted alterations of LRP1B as accounting for a high proportion of PCa and found more frequent alterations in CDH1 in Chinese PCa. Of these, only CDH1 alteration was associated with rapid biochemical recurrence (BCR). However, we verified that TP53 status was at the core of the genomic alteration landscape in Chinese HNPC with putative driver mutations because of the strong connections with other signaling pathways. The mutually exclusive relationship between alterations in TP53 and Wnt/CTNNB1 further molecularly characterizes subsets of prostate cancers. Moreover, the alteration of KMT2C was more likely to co-occur with TP53 alteration, indicating a more aggressive phenotype of PCa, which was associated with sensitivity to treatment with poly ADT-ribose polymerase (PARP) inhibitors.
Detection of TP53 alterations has clinical utility for guiding precision cancer therapy for HNPC, especially in the Chinese population.
前列腺癌（PCa）在临床和基因组特征上存在种族差异，亚洲 PCa 患者在诊断时通常表现出更具侵袭性的表型。TP53 作为 PCa 的预后生物标志物在西方人群中已得到充分研究。然而，迄今为止，尚无研究探讨 TP53 在中西方人群原发性去势治疗前列腺癌（HNPC）差异中的作用。
我们收集了前列腺肿瘤和匹配的正常组织或血液样本，对 94 例中国原发性局限性 HNPC 样本进行了靶向下一代测序，并将这些基因组谱与临床结果相关联。OncoKB 知识库用于识别和分类可操作的改变。
中国 HNPC 样本中 PTEN、CDK12 和 SPOP 的异常与西方样本相似。然而，我们证明了高频 TP53 改变（21/94）与中国 HNPC 中较高比例的 Wnt 信号通路改变（15/94）之间存在关联。此外，我们强调了 LRP1B 的改变占 PCa 的很大比例，并发现中国 PCa 中 CDH1 的改变更为频繁。其中，只有 CDH1 的改变与快速生化复发（BCR）相关。然而，我们验证了 TP53 状态是中国 HNPC 基因组改变景观的核心，因为它与其他信号通路有很强的联系，存在潜在的驱动突变。TP53 和 Wnt/CTNNB1 改变之间的互斥关系进一步从分子上描述了前列腺癌的亚群。此外，KMT2C 的改变更有可能与 TP53 的改变同时发生，这表明 PCa 的表型更具侵袭性，与多聚 ADT-核糖聚合酶（PARP）抑制剂治疗的敏感性相关。
检测 TP53 改变对指导 HNPC 的精准癌症治疗具有临床意义，特别是在中国人群中。
