Department of Radiology, Clinical College of The Affiliated Central Hospital, Lishui University, Lishui, China.
Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Institute of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.
Technol Cancer Res Treat. 2023 Jan-Dec;22:15330338231195494. doi: 10.1177/15330338231195494.
Hypoxia is known to play a critical role in tumor occurrence, progression, prognosis, and therapy resistance. However, few studies have investigated hypoxia markers for diagnosing and predicting prognosis in colon adenocarcinoma (COAD). This study aims to identify a hypoxia genes-based biomarker for predicting COAD patients' prognosis and response to immunotherapy on an individual basis. Hypoxia-related genes were extracted from the Molecular Signatures Database. Gene expression, clinical data, and mutation data of COAD were collected retrospectively from the Cancer Genome Atlas, the Gene Expression Omnibus, and the International Cancer Genome Consortium databases. Univariate and multivariate cox regression, and the least absolute shrinkage and selection operator method were used to select the genes most associated with the prognosis of COAD patients. Kaplan-Meier survival analysis, receiver operating characteristic curves, calibration curves, and decision curve analyses were performed to validate the efficacy of the signature in predicting the prognosis of COAD patients. EdU incorporation assays, cell survival assays, western blot assays, and trans-well invasion assays were performed to further confirm the function of the screened genes in tumorigenesis. ENO3 and KDM3A were identified as key genes for constructing prognostic and diagnostic signatures, which were found to be independent risk factors for predicting the prognosis and diagnosis of COAD patients. Using these signatures, COAD patients could be stratified into high-risk and low-risk groups, with the latter exhibiting better overall survival outcomes. Moreover, the high-risk group displayed elevated levels of immune checkpoint genes and tumor mutation burden, indicating that these patients may benefit from immune checkpoint inhibitor therapy. The signature developed in this study demonstrates excellent efficacy in prognosticating the outcomes of COAD patients. Moreover, it can serve as a valuable tool for clinicians to identify COAD patients who are suitable for ICI therapy.
缺氧被认为在肿瘤的发生、进展、预后和治疗耐药中起着关键作用。然而，很少有研究探讨缺氧标志物在诊断和预测结肠腺癌（COAD）患者预后中的作用。本研究旨在确定一种基于缺氧基因的生物标志物，用于预测 COAD 患者的预后，并在个体基础上预测对免疫治疗的反应。从分子特征数据库中提取了缺氧相关基因。从癌症基因组图谱、基因表达综合数据库和国际癌症基因组联合会数据库中回顾性收集了 COAD 的基因表达、临床数据和突变数据。采用单变量和多变量 cox 回归以及最小绝对收缩和选择算子方法，选择与 COAD 患者预后最相关的基因。进行 Kaplan-Meier 生存分析、受试者工作特征曲线、校准曲线和决策曲线分析，以验证该标志物预测 COAD 患者预后的疗效。进行 EdU 掺入试验、细胞生存试验、western blot 试验和 Transwell 侵袭试验，以进一步证实筛选出的基因在肿瘤发生中的作用。ENO3 和 KDM3A 被确定为构建预后和诊断特征的关键基因，它们被发现是预测 COAD 患者预后和诊断的独立危险因素。使用这些特征，COAD 患者可以分为高危和低危组，后者表现出更好的总生存结果。此外，高危组显示出更高水平的免疫检查点基因和肿瘤突变负担，表明这些患者可能受益于免疫检查点抑制剂治疗。本研究中开发的特征在预测 COAD 患者的预后方面表现出优异的疗效。此外，它可以作为临床医生的有用工具，用于识别适合 ICI 治疗的 COAD 患者。
