Department of Urology, Peking University First Hospital Institute of Urology, National Urological Cancer Center, Peking University, Beijing, China.
Pathol Oncol Res. 2021 Sep 27;27:1609968. doi: 10.3389/pore.2021.1609968. eCollection 2021.
Therapy-related neuroendocrine prostate cancer (NEPC) is a lethal castration-resistant prostate cancer (CRPC) subtype that, at present, lacks well-characterized molecular biomarkers. The clinical diagnosis of this disease is dependent on biopsy and histological assessment: methods that are experience-based and easily misdiagnosed due to tumor heterogeneity. The development of robust diagnostic tools for NEPC may assist clinicians in making medical decisions on the choice of continuing anti-androgen receptor therapy or switching to platinum-based chemotherapy. Gene expression profiles and clinical characteristics data of 208 samples of metastatic CRPC, including castration-resistant prostate adenocarcinoma (CRPC-adeno) and castration-resistant neuroendocrine prostate adenocarcinoma (CRPC-NE), were obtained from the prad_su2c_2019 dataset. Weighted Gene Co-expression Network Analysis (WGCNA) was subsequently used to construct a free-scale gene co-expression network to study the interrelationship between the potential modules and clinical features of metastatic prostate adenocarcinoma and to identify hub genes in the modules. Furthermore, the least absolute shrinkage and selection operator (LASSO) regression analysis was used to build a model to predict the clinical characteristics of CRPC-NE. The findings were then verified in the nepc_wcm_2016 dataset. A total of 51 co-expression modules were successfully constructed using WGCNA, of which three co-expression modules were found to be significantly associated with the neuroendocrine features and the NEPC score. In total, four novel genes, including NPTX1, PCSK1, ASXL3, and TRIM9, were all significantly upregulated in NEPC compared with the adenocarcinoma samples, and these genes were all associated with the neuroactive ligand receptor interaction pathway. Next, the expression levels of these four genes were used to construct an NEPC diagnosis model, which was successfully able to distinguish CRPC-NE from CRPC-adeno samples in both the training and the validation cohorts. Moreover, the values of the area under the receiver operating characteristic (AUC) were 0.995 and 0.833 for the training and validation cohorts, respectively. The present study identified four specific novel biomarkers for therapy-related NEPC, and these biomarkers may serve as an effective tool for the diagnosis of NEPC, thereby meriting further study.
治疗相关神经内分泌前列腺癌（NEPC）是一种致命的去势抵抗性前列腺癌（CRPC）亚型，目前缺乏特征明确的分子生物标志物。这种疾病的临床诊断依赖于活检和组织学评估：这些方法是基于经验的，并且由于肿瘤异质性很容易误诊。开发用于 NEPC 的强大诊断工具可能有助于临床医生在继续抗雄激素受体治疗或切换到铂类化疗之间做出医疗决策。
从 prad_su2c_2019 数据集获得了 208 个转移性 CRPC 样本的基因表达谱和临床特征数据，包括去势抵抗性前列腺腺癌（CRPC-adeno）和去势抵抗性神经内分泌前列腺腺癌（CRPC-NE）。随后使用加权基因共表达网络分析（WGCNA）构建了一个无尺度基因共表达网络，以研究转移性前列腺腺癌中潜在模块与临床特征之间的相互关系，并鉴定模块中的枢纽基因。此外，还使用最小绝对收缩和选择算子（LASSO）回归分析构建了预测 CRPC-NE 临床特征的模型。然后在 nepc_wcm_2016 数据集上验证了这些发现。
使用 WGCNA 成功构建了 51 个共表达模块，其中 3 个共表达模块与神经内分泌特征和 NEPC 评分显著相关。共有 4 个新基因，包括 NPTX1、PCSK1、ASXL3 和 TRIM9，在 NEPC 中与腺癌样本相比均显著上调，这些基因均与神经活性配体受体相互作用途径相关。接下来，使用这四个基因的表达水平构建了一个 NEPC 诊断模型，该模型能够成功区分训练和验证队列中的 CRPC-NE 和 CRPC-adeno 样本。此外，训练和验证队列的接收器工作特征（AUC）值分别为 0.995 和 0.833。
本研究鉴定了治疗相关 NEPC 的四个特定新型生物标志物，这些标志物可能成为 NEPC 诊断的有效工具，值得进一步研究。
