Cai Xintong, Lin Jie, Liu Li, Zheng Jianfeng, Liu Qinying, Ji Liyan, Sun Yang
Department of Gynecology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China.
Fujian Provincial Key Laboratory of Tumor Biotherapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, China.
BMC Cancer. 2024 Apr 23;24(1):515. doi: 10.1186/s12885-024-12245-2.
Ovarian cancer (OC) is a gynecological malignancy tumor with high recurrence and mortality rates. Programmed cell death (PCD) is an essential regulator in cancer metabolism, whose functions are still unknown in OC. Therefore, it is vital to determine the prognostic value and therapy response of PCD-related genes in OC.
By mining The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) and Genecards databases, we constructed a prognostic PCD-related genes model and performed Kaplan-Meier (K-M) analysis and Receiver Operating Characteristic (ROC) curve for its predictive ability. A nomogram was created via Cox regression. We validated our model in train and test sets. Quantitative real-time PCR (qRT-PCR) was applied to identify the expression of our model genes. Finally, we analyzed functional analysis, immune infiltration, genomic mutation, tumor mutational burden (TMB) and drug sensitivity of patients in low- and high-risk group based on median scores.
A ten-PCD-related gene signature including protein phosphatase 1 regulatory subunit 15 A (PPP1R15A), 8-oxoguanine-DNA glycosylase (OGG1), HECT and RLD domain containing E3 ubiquitin protein ligase family member 1 (HERC1), Caspase-2.(CASP2), Caspase activity and apoptosis inhibitor 1(CAAP1), RB transcriptional corepressor 1(RB1), Z-DNA binding protein 1 (ZBP1), CD3-epsilon (CD3E), Clathrin heavy chain like 1(CLTCL1), and CCAAT/enhancer-binding protein beta (CEBPB) was constructed. Risk score performed well with good area under curve (AUC) (AUC =0.728, AUC = 0.730). The nomogram based on risk score has good performance in predicting the prognosis of OC patients (AUC =0.781, AUC =0.759, AUC = 0.670). Kyoto encyclopedia of genes and genomes (KEGG) analysis showed that the erythroblastic leukemia viral oncogene homolog (ERBB) signaling pathway and focal adhesion were enriched in the high-risk group. Meanwhile, patients with high-risk scores had worse OS. In addition, patients with low-risk scores had higher immune-infiltrating cells and enhanced expression of checkpoints, programmed cell death 1 ligand 1 (PD-L1), indoleamine 2,3-dioxygenase 1 (IDO-1) and lymphocyte activation gene-3 (LAG3), and were more sensitive to A.443,654, GDC.0449, paclitaxel, gefitinib and cisplatin. Finally, qRT-PCR confirmed RB1, CAAP1, ZBP1, CEBPB and CLTCL1 over-expressed, while PPP1R15A, OGG1, CASP2, CD3E and HERC1 under-expressed in OC cell lines.
Our model could precisely predict the prognosis, immune status and drug sensitivity of OC patients.
卵巢癌（OC）是一种复发率和死亡率都很高的妇科恶性肿瘤。程序性细胞死亡（PCD）是癌症代谢中的一个重要调节因子，其在OC中的功能尚不清楚。因此，确定PCD相关基因在OC中的预后价值和治疗反应至关重要。
通过挖掘癌症基因组图谱（TCGA）、基因型-组织表达（GTEx）和基因卡片数据库，我们构建了一个与PCD相关的预后基因模型，并对其预测能力进行了Kaplan-Meier（K-M）分析和受试者工作特征（ROC）曲线分析。通过Cox回归创建了一个列线图。我们在训练集和测试集中验证了我们的模型。应用定量实时PCR（qRT-PCR）来鉴定我们模型基因的表达。最后，我们基于中位数分数分析了低风险和高风险组患者的功能分析、免疫浸润、基因组突变、肿瘤突变负担（TMB）和药物敏感性。
构建了一个包含蛋白磷酸酶1调节亚基15 A（PPP1R15A）、8-氧鸟嘌呤-DNA糖基化酶（OGG1）、含HECT和RLD结构域的E3泛素蛋白连接酶家族成员1（HERC1）、半胱天冬酶-2（CASP2）、半胱天冬酶活性和凋亡抑制剂1（CAAP1）、RB转录共抑制因子1（RB1）、Z-DNA结合蛋白1（ZBP1）、CD3-ε（CD3E）、网格蛋白重链样1（CLTCL1）和CCAAT/增强子结合蛋白β（CEBPB）的与PCD相关的十个基因特征。风险评分表现良好，曲线下面积（AUC）良好（AUC = 0.728，AUC = 0.730）。基于风险评分的列线图在预测OC患者预后方面表现良好（AUC = 0.781，AUC = 0.759，AUC = 0.670）。京都基因与基因组百科全书（KEGG）分析表明，高风险组中富集了成红细胞白血病病毒癌基因同源物（ERBB）信号通路和粘着斑。同时，高风险评分的患者总生存期较差。此外，低风险评分的患者免疫浸润细胞较多，检查点、程序性细胞死亡1配体1（PD-L1）、吲哚胺2,3-双加氧酶1（IDO-1）和淋巴细胞激活基因-3（LAG3）的表达增强，并且对A.443,654、GDC.0449、紫杉醇、吉非替尼和顺铂更敏感。最后，qRT-PCR证实RB1、CAAP1、ZBP1、CEBPB和CLTCL1在OC细胞系中过表达，而PPP1R15A、OGG1、CASP2和HERC1在OC细胞系中低表达。
我们的模型可以准确预测OC患者的预后、免疫状态和药物敏感性。
