Department of General surgery, The People's Hospital of Chizhou, Chizhou, Anhui Province, China.
Department of Nursing, The People's Hospital of Chizhou, Chizhou, Anhui Province, China.
Cell Cycle. 2023 Nov;22(21-22):2392-2408. doi: 10.1080/15384101.2023.2293594. Epub 2024 Jan 18.
Homologous repair deficiency (HRD) impedes double-strand break repair, which is a common driver of carcinogenesis. Positive HRD status can be used as theranostic markers of response to platinum- and PARP inhibitor-based chemotherapies. Here, we aimed to fully investigate the therapeutic and prognostic potential of HRD in pancreatic adenocarcinoma (PAAD) and identify effective biomarkers related to HRD using comprehensive bioinformatics analysis. The HRD score was defined as the unweighted sum of the LOH, TAI, and LST scores, and it was obtained based on the previous literature. To characterize PAAD immune infiltration subtypes, the "ConsensusClusterPlus" package in R was used to conduct unsupervised clustering. A WGCNA was conducted to elucidate the gene coexpression modules and hub genes in the HRD-related gene module of PAAD. The functional enrichment study was performed using Metascape. LASSO analysis was performed using the "glmnet" package in R, while the random forest algorithm was realized using the "randomForest" package in R. The prognostic variables were evaluated using univariate Cox analysis. The prognostic risk model was built using the LASSO approach. ROC curve and KM survival analyses were performed to assess the prognostic potential of the risk model. The half-maximal inhibitory concentration (IC50) of the PARP inhibitors was estimated using the "pRRophetic" package in R and the Genomics of Drug Sensitivity in Cancer database. The "rms" package in R was used to create the nomogram. A high HRD score indicated a poor prognosis and an advanced clinical process in PAAD patients. PAAD tumors with high HRD levels revealed significant T helper lymphocyte depletion, upregulated levels of cancer stem cells, and increased sensitivity to rucaparib, Olaparib, and veliparib. Using WGCNA, 11 coexpression modules were obtained. The red module and 122 hub genes were identified as the most correlated with HRD in PAAD. Functional enrichment analysis revealed that the 122 hub genes were mainly concentrated in cell cycle pathways. One novel HRD-related gene signature consisting of CKS1B, HJURP, and TPX2 were screened via LASSO analysis and a random forest algorithm, and they were validated using independent validation sets. No direct association between HRD and , , or has not been reported in the literature so far. Thus, these findings indicated that , , and have potential as diagnostic and prognostic biomarkers for PAAD. We constructed a novel HRD-related prognostic model that provides new insights into PAAD prognosis and immunotherapy. Based on bioinformatics analysis, we comprehensively explored the therapeutic and prognostic potential of HRD in PAAD. One novel HRD-related gene signature consisting of CKS1B, HJURP, and TPX2 were identified through the combination of WGCNA, LASSO analysis and a random forest algorithm. A novel HRD-related risk model that can predict clinical prognosis and immunotherapeutic response in PAAD patients was constructed.
同源重组缺陷（HRD）阻碍双链断裂修复，这是致癌的常见驱动因素。HRD 阳性状态可用作对铂类和 PARP 抑制剂为基础的化疗反应的治疗诊断标志物。在这里，我们旨在通过综合生物信息学分析，全面研究 HRD 在胰腺导管腺癌（PAAD）中的治疗和预后潜力，并确定与 HRD 相关的有效生物标志物。HRD 评分定义为 LOH、TAI 和 LST 评分的未加权总和，根据先前的文献获得。为了描述 PAAD 的免疫浸润亚型，使用 R 中的“ConsensusClusterPlus”软件包进行无监督聚类。进行 WGCNA 以阐明 PAAD 中 HRD 相关基因模块中的基因共表达模块和枢纽基因。使用 Metascape 进行功能富集研究。使用 R 中的“glmnet”软件包进行 LASSO 分析，使用 R 中的“randomForest”软件包实现随机森林算法。使用单因素 Cox 分析评估预后变量。使用 LASSO 方法构建预后风险模型。使用 ROC 曲线和 KM 生存分析评估风险模型的预后潜力。使用 R 中的“pRRophetic”软件包和癌症基因组药物敏感性数据库估计 PARP 抑制剂的半最大抑制浓度（IC50）。使用 R 中的“rms”软件包创建列线图。高 HRD 评分表明 PAAD 患者预后不良且临床进程较晚。PAAD 肿瘤中 HRD 水平较高，表现出显著的辅助性 T 淋巴细胞耗竭、癌症干细胞水平上调以及对鲁卡帕利、奥拉帕利和 veliparib 的敏感性增加。使用 WGCNA，获得了 11 个共表达模块。红色模块和 122 个枢纽基因被确定为与 PAAD 中 HRD 最相关的基因。功能富集分析表明，122 个枢纽基因主要集中在细胞周期途径中。通过 LASSO 分析和随机森林算法筛选出由 CKS1B、HJURP 和 TPX2 组成的新型 HRD 相关基因特征，并使用独立验证集进行验证。迄今为止，文献中尚未报道 HRD 与 、 或 之间存在直接关联。因此，这些发现表明 、 和 可能是 PAAD 的诊断和预后生物标志物。我们构建了一个新的 HRD 相关预后模型，为 PAAD 预后和免疫治疗提供了新的见解。基于生物信息学分析，我们全面探讨了 HRD 在 PAAD 中的治疗和预后潜力。通过 WGCNA、LASSO 分析和随机森林算法的组合，确定了由 CKS1B、HJURP 和 TPX2 组成的新型 HRD 相关基因特征。构建了一种新的 HRD 相关风险模型，可预测 PAAD 患者的临床预后和免疫治疗反应。
