Department of Laboratory Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
Front Immunol. 2022 Jun 10;13:906889. doi: 10.3389/fimmu.2022.906889. eCollection 2022.
Patients with lung adenocarcinoma (LUAD) exhibit significant heterogeneity in therapeutic responses and overall survival (OS). In recent years, accumulating research has uncovered the critical roles of hypoxia in a variety of solid tumors, but its role in LUAD is not currently fully elucidated. This study aims to discover novel insights into the mechanistic and therapeutic implications of the hypoxia genes in LUAD cancers by exploring the potential association between hypoxia and LUAD.
Four machine learning approaches were implemented to screen out potential hypoxia-related genes for the prognosis of LUAD based on gene expression profile of LUAD samples obtained from The Cancer Genome Atlas (TCGA), then validated by six cohorts of validation datasets. The risk score derived from the hypoxia-related genes was proven to be an independent factor by using the univariate and multivariate Cox regression analyses and Kaplan-Meier survival analyses. Hypoxia-related mechanisms based on tumor mutational burden (TMB), the immune activity, and therapeutic value were also performed to adequately dig deeper into the clinical value of hypoxia-related genes. Finally, the expression level of hypoxia genes was validated at protein level and clinical samples from LUAD patients at transcript levels.
All patients in TCGA and GEO-LUAD group were distinctly stratified into low- and high-risk groups based on the risk score. Survival analyses demonstrated that our risk score could serve as a powerful and independent risk factor for OS, and the nomogram also exhibited high accuracy. LUAD patients in high-risk group presented worse OS, lower TMB, and lower immune activity. We found that the model is highly sensitive to immune features. Moreover, we revealed that the hypoxia-related genes had potential therapeutic value for LUAD patients based on the drug sensitivity and chemotherapeutic response prediction. The protein and gene expression levels of 10 selected hypoxia gene also showed significant difference between LUAD tumors tissues and normal tissues. The validation experiment showed that the gene transcript levels of most of their genes were consistent with the levels of their translated proteins.
Our study might contribute to the optimization of risk stratification for survival and personalized management of LUAD patients by using the hypoxia genes, which will provide a valuable resource that will guide both mechanistic and therapeutic implications of the hypoxia genes in LUAD cancers.
肺腺癌（LUAD）患者在治疗反应和总生存期（OS）方面存在显著异质性。近年来，越来越多的研究揭示了缺氧在各种实体肿瘤中的关键作用，但目前尚不完全清楚其在 LUAD 中的作用。本研究旨在通过探索潜在的缺氧与 LUAD 之间的关联，发现 LUAD 癌症中缺氧基因的机制和治疗意义的新见解。
基于从癌症基因组图谱（TCGA）获得的 LUAD 样本的基因表达谱，实施了四种机器学习方法来筛选出潜在的与 LUAD 预后相关的缺氧基因，然后通过六个 LUAD 验证数据集进行验证。通过单因素和多因素 Cox 回归分析和 Kaplan-Meier 生存分析证明，从缺氧相关基因得出的风险评分是一个独立的因素。还进行了基于肿瘤突变负担（TMB）、免疫活性和治疗价值的缺氧相关机制分析，以充分挖掘缺氧相关基因的临床价值。最后，在蛋白质水平和 LUAD 患者的临床样本中转录水平验证了缺氧基因的表达水平。
TCGA 和 GEO-LUAD 组中的所有患者均根据风险评分明显分为低风险和高风险组。生存分析表明，我们的风险评分可以作为 OS 的强大且独立的危险因素，并且列线图也具有很高的准确性。高风险组的 LUAD 患者的 OS 更差，TMB 更低，免疫活性更低。我们发现该模型对免疫特征高度敏感。此外，我们还发现基于药物敏感性和化疗反应预测，缺氧相关基因对 LUAD 患者具有潜在的治疗价值。从 LUAD 肿瘤组织和正常组织中也观察到 10 个选定的缺氧基因的蛋白质和基因表达水平存在显著差异。验证实验表明，它们的大多数基因的基因转录水平与其翻译蛋白的水平一致。
我们的研究通过使用缺氧基因可能有助于 LUAD 患者的生存风险分层优化和个性化管理，为 LUAD 癌症中缺氧基因的机制和治疗意义提供有价值的资源。
