构建一种新型的与线粒体相关的基因特征，用于评估胃腺癌的肿瘤免疫微环境并预测生存。
Constructing a novel mitochondrial-related gene signature for evaluating the tumor immune microenvironment and predicting survival in stomach adenocarcinoma.
机构信息
Department of Cell Biology and Medical Genetics, School of Basic Medical Science, Shanxi Medical University, Taiyuan, 030001, China.
Department of Pathology, Laboratory of Translational Medicine Research, Deyang People's Hospital, Deyang, China.
出版信息
J Transl Med. 2023 Mar 13;21(1):191. doi: 10.1186/s12967-023-04033-6.
BACKGROUND
The incidence and mortality of gastric cancer ranks fifth and fourth worldwide among all malignancies, respectively. Accumulating evidences have revealed the close relationship between mitochondrial dysfunction and the initiation and progression of stomach cancer. However, rare prognostic models for mitochondrial-related gene risk have been built up in stomach cancer.
METHODS
In current study, the expression and prognostic value of mitochondrial-related genes in stomach adenocarcinoma (STAD) patients were systematically analyzed to establish a mitochondrial-related risk model based on available TCGA and GEO databases. The tumor microenvironment (TME), immune cell infiltration, tumor mutation burden, and drug sensitivity of gastric adenocarcinoma patients were also investigated using R language, GraphPad Prism 8 and online databases.
RESULTS
We established a mitochondrial-related risk prognostic model including NOX4, ALDH3A2, FKBP10 and MAOA and validated its predictive power. This risk model indicated that the immune cell infiltration in high-risk group was significantly different from that in the low-risk group. Besides, the risk score was closely related to TME signature genes and immune checkpoint molecules, suggesting that the immunosuppressive tumor microenvironment might lead to poor prognosis in high-risk groups. Moreover, TIDE analysis demonstrated that combined analysis of risk score and immune score, or stromal score, or microsatellite status could more effectively predict the benefit of immunotherapy in STAD patients with different stratifications. Finally, rapamycin, PD-0325901 and dasatinib were found to be more effective for patients in the high-risk group, whereas AZD7762, CEP-701 and methotrexate were predicted to be more effective for patients in the low-risk group.
CONCLUSIONS
Our results suggest that the mitochondrial-related risk model could be a reliable prognostic biomarker for personalized treatment of STAD patients.
背景
胃癌的发病率和死亡率在所有恶性肿瘤中分别位居世界第五和第四。越来越多的证据表明，线粒体功能障碍与胃癌的发生和发展密切相关。然而，目前很少有基于线粒体相关基因风险的胃癌预后模型建立。
方法
本研究系统分析了胃腺癌（STAD）患者线粒体相关基因的表达和预后价值，基于 TCGA 和 GEO 数据库建立了一个线粒体相关风险模型。使用 R 语言、GraphPad Prism 8 和在线数据库研究胃腺癌患者的肿瘤微环境（TME）、免疫细胞浸润、肿瘤突变负担和药物敏感性。
结果
我们建立了一个包括 NOX4、ALDH3A2、FKBP10 和 MAOA 的线粒体相关风险预后模型，并验证了其预测能力。该风险模型表明，高危组的免疫细胞浸润与低危组有显著差异。此外，风险评分与 TME 特征基因和免疫检查点分子密切相关，提示免疫抑制性肿瘤微环境可能导致高危组预后不良。此外，TIDE 分析表明，联合分析风险评分和免疫评分、或基质评分、或微卫星状态可以更有效地预测不同分层的 STAD 患者免疫治疗的获益。最后，发现雷帕霉素、PD-0325901 和 dasatinib 对高危组患者更有效，而 AZD7762、CEP-701 和甲氨蝶呤则预测对低危组患者更有效。
结论
我们的研究结果表明，线粒体相关风险模型可能是 STAD 患者个体化治疗的可靠预后生物标志物。
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