Yuan Xiaolu, Zhou Jun, Zhou Liping, Huang Zudong, Wang Weiwei, Qiu Jiasheng, Yang Qiangbang, Zhang Chaohao, Ma MingHui
Department of Pathology, Maoming People's Hospital, Maoming, China.
Department of Gastrointestinal Surgery, Maoming People's Hospital, Maoming, China.
Front Genet. 2022 Jul 5;13:921163. doi: 10.3389/fgene.2022.921163. eCollection 2022.
Apoptosis is a type of cell death, which can produce abundant mediators to modify the tumor microenvironment. However, relationships between apoptosis, immunosuppression, and immunotherapy resistance of gastric cancer (GC) remain unclear. Gene expression data and matching clinical information were extracted from TCGA-STAD, GSE84437, GSE34942, GSE15459, GSE57303, ACRG/GSE62254, GSE29272, GSE26253, and IMvigor210 datasets. A consensus clustering analysis based on six apoptosis-related genes (ARGs) was performed to determine the molecular subtypes, and then an apoptosisScore was constructed based on differentially expressed and prognostic genes between molecular subtypes. Estimate R package was utilized to calculate the tumor microenvironment condition. Kaplan-Meier analysis and ROC curves were performed to further confirm the apoptosisScore efficacy. Based on six ARGs, two molecular subgroups with significantly distinct survival and immune cell infiltration were identified. Then, an apoptosisScore was built to quantify the apoptosis index of each GC patient. Next, we investigated the correlations between the clinical characteristics and apoptosisScore using logistic regression. Multivariate Cox analysis shows that low apoptosisScore was an independent predictor of poor overall survival in TCGA and ACRG datasets, and was associated with the higher pathological stage. Meanwhile, low apoptosisScore was associated with higher immune cell, higher ESTIMATEScore, higher immuneScore, higher stromalScore, higher immune checkpoint, and lower tumorpurity, which was consistent with the "immunity tidal model theory". Importantly, low apoptosisScore was sensitive to immunotherapy. In addition, GSEA indicated that several gene ontology and Kyoto Encyclopedia of Genes and Genomes items associated with apoptosis, several immune-related pathways, and JAK-STAT signal pathway were considerably enriched in the low apoptosisScore phenotype pathway. Our findings propose that low apoptosisScore is a prognostic biomarker, correlated with immune infiltrates, and sensitivity to immunotherapy in GC.
细胞凋亡是一种细胞死亡类型，它能产生大量介质来改变肿瘤微环境。然而，胃癌（GC）的细胞凋亡、免疫抑制和免疫治疗耐药性之间的关系仍不清楚。从TCGA-STAD、GSE84437、GSE34942、GSE15459、GSE57303、ACRG/GSE62254、GSE29272、GSE26253和IMvigor210数据集中提取基因表达数据和匹配的临床信息。基于六个凋亡相关基因（ARG）进行共识聚类分析以确定分子亚型，然后基于分子亚型之间差异表达和预后基因构建凋亡评分（apoptosisScore）。利用Estimate R包计算肿瘤微环境状况。进行Kaplan-Meier分析和ROC曲线以进一步确认凋亡评分的有效性。基于六个ARG，鉴定出两个生存和免疫细胞浸润明显不同的分子亚组。然后，构建凋亡评分以量化每个GC患者的凋亡指数。接下来，我们使用逻辑回归研究临床特征与凋亡评分之间的相关性。多变量Cox分析表明，低凋亡评分是TCGA和ACRG数据集中总生存期差的独立预测因子，且与更高的病理分期相关。同时，低凋亡评分与更高的免疫细胞、更高的ESTIMATEScore、更高的免疫评分、更高的基质评分、更高的免疫检查点和更低的肿瘤纯度相关，这与“免疫潮汐模型理论”一致。重要的是，低凋亡评分对免疫治疗敏感。此外，基因集富集分析（GSEA）表明，与凋亡相关的几个基因本体和京都基因与基因组百科全书条目、几个免疫相关途径以及JAK-STAT信号通路在低凋亡评分表型途径中显著富集。我们的研究结果表明，低凋亡评分是一种预后生物标志物，与免疫浸润相关，且对GC免疫治疗敏感。
