Dong Wenlei, Jing Suwei, Mu Xinxin
Department of Radiotherapy Technology Center, Harbin Medical University Cancer Hospital, Harbin, China.
The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.
J Thorac Dis. 2025 Aug 31;17(8):6214-6228. doi: 10.21037/jtd-2025-1438. Epub 2025 Aug 28.
Lung adenocarcinoma (LUAD) is the most common type of lung cancer, and has a high mortality rate. Surgical resection is the standard treatment for early stage patients; however, many patients experience recurrence or death within 5 years. Thus, reliable prognostic markers urgently need to be identified to guide clinical decisions and enhance patient outcomes. While molecular profiling has uncovered significant molecular irregularities in LUAD, existing prognostic signatures exhibit limited reproducibility and inconsistent performance across datasets. These limitations are mainly attributed to small sample sizes, technical biases, and inadequate biological context. This study aims to develop a function-derived gene signature for LUAD prognosis using a multicenter integrative analysis approach.
We used gene expression and clinical data from 1,238 curatively resected LUAD patients across 11 public datasets. A meta-discovery dataset comprising 665 patients was analyzed to extract prognostic genes from a functional perspective. Using a single-sample gene set enrichment method in pairwise comparisons, we established a multigene signature. Specifically, we identified 14 glycolysis-related prognostic genes, which were then included in the 14-gene glycolysis metabolism prognostic signature (14GM-PS).
The 14GM-PS prognostic performance was validated in two independent datasets (n=299 and n=274), both demonstrating significant differences in 5-year survival rates (log-rank P<0.001 and P=0.004, respectively). The multivariate Cox analysis results confirmed that the 14GM-PS could be used to predict patient prognosis. Further, a novel nomogram incorporating the 14GM-PS and clinicopathological factors showed improved prognostic accuracy. The patients identified as high risk by the 14GM-PS had higher hypoxia, proliferation, and stemness scores, but lower immune scores, indicating a strong association between transcriptomic characteristics and clinical outcomes. The 14GM-PS showed consistent performance across different platforms and validation cohorts.
This multicenter study showed the accuracy and stability of the 14GM-PS in predicting the prognosis of LUAD patients. This promising genomic tool could be used to guide individualized treatment decisions in LUAD patients. However, further prospective clinical validation is required before its clinical application.
肺腺癌（LUAD）是最常见的肺癌类型，死亡率很高。手术切除是早期患者的标准治疗方法；然而，许多患者在5年内会出现复发或死亡。因此，迫切需要确定可靠的预后标志物，以指导临床决策并改善患者预后。虽然分子图谱分析揭示了LUAD中显著的分子异常，但现有的预后特征在不同数据集之间的可重复性有限且性能不一致。这些局限性主要归因于样本量小、技术偏差和生物学背景不足。本研究旨在使用多中心综合分析方法开发一种用于LUAD预后的功能衍生基因特征。
我们使用了来自11个公共数据集的1238例接受根治性切除的LUAD患者的基因表达和临床数据。对一个包含665例患者的元发现数据集进行分析，从功能角度提取预后基因。使用单样本基因集富集方法进行成对比较，我们建立了一个多基因特征。具体而言，我们鉴定了14个与糖酵解相关的预后基因，然后将其纳入14基因糖酵解代谢预后特征（14GM-PS）。
14GM-PS的预后性能在两个独立数据集（n=299和n=274）中得到验证，两者均显示5年生存率存在显著差异（对数秩检验P分别<0.001和P=0.004）。多变量Cox分析结果证实14GM-PS可用于预测患者预后。此外，一个纳入14GM-PS和临床病理因素的新型列线图显示预后准确性有所提高。被14GM-PS鉴定为高风险的患者具有更高的缺氧、增殖和干性评分，但免疫评分较低，表明转录组特征与临床结果之间存在密切关联。14GM-PS在不同平台和验证队列中表现一致。
这项多中心研究显示了14GM-PS在预测LUAD患者预后方面的准确性和稳定性。这种有前景的基因组工具可用于指导LUAD患者的个体化治疗决策。然而，在其临床应用之前还需要进一步的前瞻性临床验证。
