泛胃肠道腺癌分析揭示了铁中毒相关基因的预后和免疫相关性。

IF 2.5 Q2 GASTROENTEROLOGY & HEPATOLOGY
Translational gastroenterology and hepatology Pub Date : 2025-01-17 eCollection Date: 2025-01-01 DOI:10.21037/tgh-24-15
Xiaochuan Dong, Yanyan Xie, Wenxi Chen, Mengjiang He, Hua Liu, Bin Wang, Yu Xu, Qiaoxia Zhou, Tengfei Zhu, Guoqiang Wang, Chunwei Xu, Wenxian Wang, Shangli Cai, Meili Xu, Jingjing Wang
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引用次数: 0

摘要

背景:胃肠道腺癌(GIACs)是世界范围内常见的恶性肿瘤,预后较差。以细胞内铁和脂质活性氧积累为特征的铁下沉是肿瘤发生和癌症进展的关键过程。然而,在GIAC中与铁沉有关的基因的含义仍有待阐明。本研究旨在探讨枯铁相关基因在GIAC预后和治疗中的潜在作用。方法:在我们的研究中,从癌症基因组图谱(TCGA)、癌细胞系百科全书(CCLE)、癌症药物敏感性基因组学(GDSC)和基因表达Omnibus (GEO)中获得了全面的临床、转录组和/或基因组数据。我们通过基因集变异分析(GSVA)在TCGA队列中制定了一个铁死症评分,并随后在4个GEO数据集(GSE84437、GSE17536、GSE103479和GSE19417)中进行了验证。在GDSC数据集和PRJEB25780队列中分别分析药物敏感性和免疫治疗疗效。结果:在训练队列中,铁残评分与良好的总生存率显著相关[TCGA: P=0.003;风险比(HR)为0.67,95%可信区间(95% CI): 0.52-0.87],四个验证队列(GSE17536: P=0.03;Hr, 0.57, 95% ci: 0.34-0.96;GSE19417: P = 0.047;Hr, 0.53, 95% ci: 0.28-1.01;GSE84437: P = 0.004;Hr, 0.68, 95% ci: 0.51-0.90;GSE103479: P = 0.03;Hr, 0.55, 95% ci: 0.32-0.96)。此外,死铁评分与DNA损伤修复途径的激活和顺铂耐药性相关。值得注意的是,低铁中毒评分的GIACs表现出免疫检查点分子(如程序性死亡-(配体)1和细胞毒性T淋巴细胞抗原-4)的表达升高,肿瘤浸润性CD8+ T细胞密度升高,并且对派姆单抗单药治疗有良好的反应。结论:我们的研究结果描述了GIACs中死铁相关基因的临床相关性,并证明了死铁评分在预测预后和免疫治疗效果方面的潜在效用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pan-gastrointestinal adenocarcinoma analysis uncovers the prognostic and immune correlates of ferroptosis-related genes.

Background: Gastrointestinal adenocarcinomas (GIACs) are common malignant tumors with poor prognosis in the world. Ferroptosis, characterized by the accumulation of intracellular iron and lipid reactive oxygen species, emerges as a pivotal process in tumorigenesis and cancer advancement. However, the implications of ferroptosis-related genes in GIAC remain to be elucidated. This study aimed at exploring the potential role of ferroptosis-related genes on the prognosis and treatment of GIAC.

Methods: In our study, comprehensive clinical, transcriptomic, and/or genomic data were acquired from The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), Genomics of Drug Sensitivity in Cancer (GDSC), and Gene Expression Omnibus (GEO). We formulated a ferroptosis-score within the TCGA cohort through gene set variation analysis (GSVA) and subsequently validated in 4 GEO datasets (GSE84437, GSE17536, GSE103479, and GSE19417). Drug sensitivity and immunotherapy efficacy were analyzed in the GDSC dataset and the PRJEB25780 cohort, respectively.

Results: The ferroptosis-score was significantly associated with favorable overall survival both in the training cohort [TCGA: P=0.003; hazard ratio (HR), 0.67, 95% confidence interval (95% CI): 0.52-0.87] and across the four validation cohorts (GSE17536: P=0.03; HR, 0.57, 95% CI: 0.34-0.96; GSE19417: P=0.047; HR, 0.53, 95% CI: 0.28-1.01; GSE84437: P=0.004; HR, 0.68, 95% CI: 0.51-0.90; GSE103479: P=0.03; HR, 0.55, 95% CI: 0.32-0.96). Furthermore, the ferroptosis-score was correlated with activation of the DNA damage repair pathway and resistance to cisplatin. Notably, GIACs with low ferroptosis-scores exhibited heightened expression of immune checkpoint molecules such as programmed death-(ligand) 1 and cytotoxic T lymphocyte antigen-4, elevated densities of tumor-infiltrating CD8+ T cells, and a favorable response to pembrolizumab monotherapy.

Conclusions: Our findings delineated the clinical relevance of ferroptosis-related genes in GIACs and demonstrated the potential utility of the ferroptosis-score in predicting prognosis and immunotherapy effectiveness.

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