近年来，中国初次诊断为晚期和转移性前列腺癌的发生率逐年增高。目前，去势激素剥夺疗法（ADT）是晚期前列腺癌的主要治疗方法。然而，经过数年的ADT治疗，大多数患者最终会进展为去势抵抗性前列腺癌（CRPC）。以往的研究主要集中在高加索人群，对东亚人群的研究很少。本研究收集了来自5例中国晚期前列腺癌患者的ADT治疗前后的肿瘤样本，进行了全外显子组测序、肿瘤异质性和克隆演化模式分析。结果显示，去势激素剥夺疗法后基因突变模式和异质性发生了显著改变。治疗后组的肿瘤突变负担（TMB）和拷贝数改变（CNA）显著降低，但突变等位基因异质性（MATH）、社会人口指数（SDI）、肿瘤内异质性（ITH）和加权基因不稳定性指数（wGII）没有显著差异。根据克隆类型和特征，五个治疗前后样本中主要克隆的存在，克隆演化模式可以进一步分为两个亚群（同质起源克隆模型或异质起源克隆模型）。"同质起源克隆模型"患者的无进展生存期（PFS）普遍较短，而"异质起源克隆模型"患者的PFS较长。PFS的延长可能与MUC7和MUC5B突变修复有关。ZNF91突变可能与对ADT的耐药性有关。我们的研究结果揭示了预测去势抵抗性的潜在遗传调控因子，并为晚期前列腺癌中的去势抵抗性过程提供了新的认识。克隆演化模式与肿瘤微环境之间的相互作用也可能在去势抵抗性中发挥作用。未来需要进行包括更多不同背景的大样本多中心研究来确认我们的结论。© 2023 BioMed Central Ltd., part of Springer Nature.

Nowadays, the incidence rate of advanced and metastatic prostate cancer at the first time of diagnosis grows higher in China yearly. At present, androgen deprivation therapy (ADT) is the primary treatment of advanced prostate cancer. However, after several years of ADT, most patients will ultimately progress to castration-resistant prostate cancer (CRPC). Previous studies mainly focus on Caucasian and very few on East Asian patients.In this study, the pre- and post-ADT tumor samples were collected from five Chinese patients with advanced prostate cancer. The whole-exome sequencing, tumor heterogeneity, and clonal evolution pattern were analyzed.The results showed that the gene mutation pattern and heterogeneity changed significantly after androgen deprivation therapy. Tumor Mutational Burden (TMB) and Copy Number Alteration (CNA) were substantially reduced in the post-treatment group, but the Mutant-allele tumor heterogeneity (MATH), Socio-Demographic Index (SDI), Intratumor heterogeneity (ITH), and weighted Genome Instability Index (wGII) had no significant difference. According to the clone types and characteristics, the presence of main clones in five pre-and post-treatment samples, the clonal evolution pattern can be further classified into two sub-groups (the Homogeneous origin clonal model or the Heterogeneous origin clonal model). The Progression-free survival (PFS) of the patients with the "Homogeneous origin clonal model" was shorter than the "Heterogeneous origin clonal model". The longer PFS might relate to MUC7 and MUC5B mutations repaired. ZNF91 mutation might be responsible for resistance to ADT resistance.Our findings revealed potential genetic regulators to predict the castration resistance and provide insights into the castration resistance processes in advanced prostate cancer. The crosstalk between clonal evolution patterns and tumor microenvironment may also play a role in castration resistance. A multicenter-research including larger populations with different background are needed to confirm our conclusion in the future.© 2023. BioMed Central Ltd., part of Springer Nature.