Yang Jing, Jin Feifan, Li Huanjuan, Shen Yuhuan, Shi Weilin, Wang Lina, Zhong Lei, Wu Gongqiang, Wu Qiaoliang, Li Yanchun
Laboratory Medicine Center, Department of Laboratory Medicine, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.
Department of Central Laboratory, Affiliated Hangzhou first people's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China.
Cancer Cell Int. 2023 Apr 16;23(1):69. doi: 10.1186/s12935-023-02913-x.
Stomach adenocarcinoma (STAD) is the third leading cause of cancer-related deaths and the fifth most prevalent malignancy worldwide. Mitochondrial respiratory chain complexes play a crucial role in STAD pathogenesis. However, how mitochondrial respiratory chain complex genes (MRCCGs) affect the prognosis and tumor microenvironment in STAD remains unclear. In this study, we systematically analyzed genetic alterations and copy number variations of different expression densities of MRCCGs, based on 806 samples from two independent STAD cohorts. Then we employed the unsupervised clustering method to classify the samples into three expression patterns based on the prognostic MRCCG expressions, and found that they were involved in different biological pathways and correlated with the clinicopathological characteristics, immune cell infiltration, and prognosis of STAD. Subsequently, we conducted a univariate Cox regression analysis to identify the prognostic value of 1175 subtype-related differentially expressed genes (DEGs) and screened out 555 prognostic-related genes. Principal component analysis was performed and developed the MG score system to quantify MRCCG patterns of STAD. The prognostic significance of MG Score was validated in three cohorts. The low MG score group, characterized by increased microsatellite instability-high (MSI-H), tumor mutation burden (TMB), PD-L1 expression, had a better prognosis. Interestingly, we demonstrated MRCCG patterns score could predict the sensitivity to ferroptosis inducing therapy. Our comprehensive analysis of MRCCGs in STAD demonstrated their potential roles in the tumor-immune-stromal microenvironment, clinicopathological features, and prognosis. Our findings highlight that MRCCGs may provide a new understanding of immunotherapy strategies for gastric cancer and provide a new perspective on the development of personalized immune therapeutic strategies for patients with STAD.
胃腺癌（STAD）是癌症相关死亡的第三大主要原因，也是全球第五大常见恶性肿瘤。线粒体呼吸链复合物在STAD发病机制中起关键作用。然而，线粒体呼吸链复合基因（MRCCGs）如何影响STAD的预后和肿瘤微环境仍不清楚。在本研究中，我们基于来自两个独立STAD队列的806个样本，系统分析了不同表达密度的MRCCGs的基因改变和拷贝数变异。然后，我们采用无监督聚类方法，根据预后MRCCG表达将样本分为三种表达模式，发现它们参与不同的生物学途径，并与STAD的临床病理特征、免疫细胞浸润和预后相关。随后，我们进行单变量Cox回归分析，以确定1175个亚型相关差异表达基因（DEGs）的预后价值，并筛选出555个预后相关基因。进行主成分分析并开发了MG评分系统，以量化STAD的MRCCG模式。MG评分的预后意义在三个队列中得到验证。低MG评分组的特征是微卫星高度不稳定（MSI-H）增加、肿瘤突变负担（TMB）、PD-L1表达增加，预后较好。有趣的是，我们证明MRCCG模式评分可以预测对铁死亡诱导治疗的敏感性。我们对STAD中MRCCGs的综合分析证明了它们在肿瘤-免疫-基质微环境、临床病理特征和预后中的潜在作用。我们的研究结果突出表明，MRCCGs可能为胃癌免疫治疗策略提供新的认识，并为STAD患者个性化免疫治疗策略的发展提供新的视角。
