Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.
Front Immunol. 2022 Jan 27;13:777724. doi: 10.3389/fimmu.2022.777724. eCollection 2022.
Currently, the impact of the circadian rhythm on the tumorigenesis and progression of prostate cancer (PCA) has yet to be understood. In this study, we first established a novel nomogram to predict PCA progression based on circadian clock (CIC)-related genes and provided insights into the tumor immune microenvironment.
The TCGA and Genecards databases were used to identify potential candidate genes. Lasso and Cox regression analyses were applied to develop a CIC-related gene signature. The tumor immune microenvironment was evaluated through appropriate statistical methods and the GSCALite database.
Ten genes were identified to construct a gene signature to predict progression probability for patients with PCA. Patients with high-risk scores were more prone to progress than those with low-risk scores (hazard ratio (HR): 4.11, 95% CI: 2.66-6.37; risk score cut-off: 1.194). CLOCK, PER (1, 2, 3), CRY2, NPAS2, RORA, and ARNTL showed a higher correlation with anti-oncogenes, while CSNK1D and CSNK1E presented a greater relationship with oncogenes. Overall, patients with higher risk scores showed lower mRNA expression of PER1, PER2, and CRY2 and higher expression of CSNK1E. In general, tumor samples presented higher infiltration levels of macrophages, T cells and myeloid dendritic cells than normal samples. In addition, tumor samples had higher immune scores, lower stroma scores and lower microenvironment scores than normal samples. Notably, patients with higher risk scores were associated with significantly lower levels of neutrophils, NK cells, T helper type 1, and mast cells. There was a positive correlation between the risk score and the tumor mutation burden (TMB) score, and patients with higher TMB scores were more prone to progress than those with lower TMB scores. Likewise, we observed similar results regarding the correlation between the microsatellite instability (MSI) score and the risk score and the impact of the MSI score on the progression-free interval. We observed that anti-oncogenes presented a significantly positive correlation with PD-L1, PD-L2, TIGIT and SIGLEC15, especially PD-L2.
We identified ten prognosis-related genes as a promising tool for risk stratification in PCA patients from the fresh perspective of CIC.
目前，关于生物钟（circadian clock，CIC）对前列腺癌（prostate cancer，PCA）发生和进展的影响尚未完全明确。本研究首次建立了一个基于 CIC 相关基因的预测 PCA 进展的新型列线图，并探讨了肿瘤免疫微环境。
通过 TCGA 和 Genecards 数据库筛选潜在的候选基因，采用 Lasso 和 Cox 回归分析构建 CIC 相关基因特征，通过适当的统计学方法和 GSCALite 数据库评估肿瘤免疫微环境。
共筛选出 10 个基因构建 PCA 患者进展概率预测的基因签名，高风险评分患者较低风险评分患者更易进展（风险比（hazard ratio，HR）：4.11，95%CI：2.66-6.37；风险评分截断值：1.194）。CLOCK、PER（1、2、3）、CRY2、NPAS2、RORA 和 ARNTL 与抑癌基因的相关性更高，而 CSNK1D 和 CSNK1E 与癌基因的相关性更高。总体而言，高风险评分患者的 PER1、PER2 和 CRY2 的 mRNA 表达较低，CSNK1E 的表达较高。一般来说，肿瘤样本比正常样本有更高的巨噬细胞、T 细胞和髓样树突状细胞浸润水平。此外，肿瘤样本的免疫评分较高，基质评分和微环境评分较低。值得注意的是，高风险评分患者的中性粒细胞、NK 细胞、辅助性 T 细胞 1 和肥大细胞水平显著较低。风险评分与肿瘤突变负荷（tumor mutation burden，TMB）评分呈正相关，TMB 评分较高的患者较 TMB 评分较低的患者更易进展。同样，我们观察到 MSI 评分与风险评分之间存在相似的相关性，以及 MSI 评分对无进展生存期的影响。我们发现抑癌基因与 PD-L1、PD-L2、TIGIT 和 SIGLEC15 呈显著正相关，尤其是 PD-L2。
我们从 CIC 的新视角确定了 10 个与预后相关的基因，作为 PCA 患者风险分层的有前途的工具。
