Liver Disease Center, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, 266003, China.
Department of Clinical Hematology, Qingdao University School of Medicine, China.
Comput Biol Med. 2022 Oct;149:106037. doi: 10.1016/j.compbiomed.2022.106037. Epub 2022 Aug 27.
Whether pyroptosis, apoptosis, and necroptosis (PAN) molecular subtypes exist in gastric cancer (GC) remains unclear.
Seven independent cohorts including a total of 1901 GC patients were enrolled in our research. TCGA (n = 371) and GSE84437 (n = 433) were combined into one cohort (n = 804) to screen for prognosis-related PAN genes using a univariate Cox regression analysis. The R package "ConsensusClusterPlus" was applied to conduct a clustering analysis of the combination set based on prognosis-related PAN genes. The R package "limma" was used for the identification of differentially expressed genes (DEGs) between different PAN clusters (FDR <0.05 and |logFC|>1). The combined cohort was randomly divided into a training group (n = 484) and a test group (n = 320) at a ratio of 6:4 to establish and verify the prognostic model. A univariate Cox regression analysis, least absolute shrinkage and selection operator method (LASSO) regression analysis, and multivariate Cox regression analysis were used for the identification of prognostic genes and the construction of risk scores. Another five independent cohorts (GSE62254, n = 300; GSE15459, n = 191; GSE26901, n = 109; GSE26253, n = 432; and GSE13861, n = 65) were used for external validation to verify the accuracy and stability of the prognostic signature.
The internal and external validation demonstrated that the 5-gene risk score (LOXL4, SLCO2A1, CST2, PDK4, and MMP11) was an effective instrument for the prognostic risk classification of GC patients. The overall survival (OS) and relapse-free survival (RFS) in the high-risk group were significantly lower than those in the low-risk group and were accompanied by a larger proportion of macrophage and regulatory T cell infiltration. The low-risk group had a good prognosis, with a high tumor mutation burden (TMB), strong cytolytic activity, and a higher proportion of activated CD4 T cell infiltration. In addition, compared with the low-risk group, the cancer-related pathways in the high-risk group were overactivated, and the function of DNA damage repair (DDR) was significantly weakened. Regarding drug sensitivity, the high-risk group was more suitable for targeted drugs, such as axitinib, lapatinib, and nilotinib. The low-risk group was more sensitive to chemotherapy, such as cisplatin, gemcitabine, and vinorelbine.
A universally applicable prognostic signature of GC is proposed in this research based on pyroptosis, apoptosis, and necroptosis (PAN) molecular subtypes.
胃癌（GC）中是否存在细胞焦亡、细胞凋亡和坏死性凋亡（PAN）分子亚型尚不清楚。
本研究共纳入了 7 个独立的队列，共包含 1901 例 GC 患者。TCGA（n=371）和 GSE84437（n=433）被合并为一个队列（n=804），通过单因素 Cox 回归分析筛选与预后相关的 PAN 基因。使用 R 包“ConsensusClusterPlus”基于与预后相关的 PAN 基因对合并队列进行聚类分析。使用 R 包“limma”识别不同 PAN 聚类之间的差异表达基因（FDR<0.05，|logFC|>1）。将合并队列按 6:4 的比例随机分为训练组（n=484）和测试组（n=320），以建立和验证预后模型。使用单因素 Cox 回归分析、最小绝对收缩和选择算子方法（LASSO）回归分析和多因素 Cox 回归分析确定预后基因并构建风险评分。另外，还使用了另外 5 个独立的队列（GSE62254，n=300；GSE15459，n=191；GSE26901，n=109；GSE26253，n=432；GSE13861，n=65）进行外部验证，以验证预后特征的准确性和稳定性。
内部和外部验证均表明，5 个基因风险评分（LOXL4、SLCO2A1、CST2、PDK4 和 MMP11）是 GC 患者预后风险分类的有效工具。高危组的总生存期（OS）和无复发生存期（RFS）明显低于低危组，并且巨噬细胞和调节性 T 细胞浸润比例较大。低危组预后良好，肿瘤突变负担（TMB）较高，细胞溶解活性较强，激活的 CD4 T 细胞浸润比例较高。此外，与低危组相比，高危组的癌症相关途径过度激活，DNA 损伤修复（DDR）功能明显减弱。在药物敏感性方面，高危组更适合使用靶向药物，如 axitinib、lapatinib 和 nilotinib。低危组对化疗药物更敏感，如顺铂、吉西他滨和长春瑞滨。
本研究基于细胞焦亡、细胞凋亡和坏死性凋亡（PAN）分子亚型提出了一种普遍适用的 GC 预后标志物。
