Lung adenocarcinoma (LUAD) exhibits significant molecular heterogeneity; however, previous studies have not fully explored its classification into distinct molecular subtypes. Here, we identified LUAD-significant chromosomal instability (CIN) phenotype genes (n= 24) using a TCGA-LUAD cohort (n= 592) and evaluated their ability to predict pathologic grade. Unsupervised clustering and principal component analysis revealed that LUAD patients could be classified into CIN phenotype-related subtypes (GroupLow, GroupModerate, and GroupHigh), each exhibiting distinct transcriptomic patterns. Notably, the GroupHighshowed significantly poor overall survival [OS; hazard ratio (HR) = 1.43,p-value < 10−3] and disease-free survival (DFS; HR = 1.27,p-value < 10−3). Univariate and multivariate analysis confirmed that its expression status was an independent prognostic predictor (p-value < 10−3, HR = 2.18, 95% C.I = 1.26–3.76) of the clinical outcomes, outperforming pathologic grade (p-value < 10−3, HR = 1.2, 95% C.I = 1.08–1.33). Moreover, analysis of surfactant metabolism-related genes revealed higher expression in the GroupLow, which was associated with a favorable prognosis. By integrating multiple independent cohorts (n= 779), we validated these findings and confirmed that CIN phenotype gene status serves as a critical prognostic marker in LUAD. Furthermore, genomic profiling showed that the GroupHighexhibited frequent mutations in key genes such asKEAP1,LYST,SETD2, andTP53, with oncogenes in this group preferentially showing copy number gains. Our study highlights the significance of CIN phenotype gene status as a predictor of LUAD prognosis and its association with transcriptomic and genomic alterations, paving the way for further clinical validation and potential therapeutic interventions.
肺腺癌（LUAD）表现出显著的分子异质性，但先前研究尚未充分探索其不同分子亚型的分类。本研究基于TCGA-LUAD队列（n=592）鉴定出24个肺腺癌特异性染色体不稳定性（CIN）表型基因，并评估其预测病理分级的效能。通过无监督聚类和主成分分析发现，肺腺癌患者可划分为CIN表型相关亚型（低危组、中危组和高危组），各亚型呈现独特的转录组特征。值得注意的是，高危组患者的总生存期（OS；风险比HR=1.43，p值<10⁻³）和无病生存期（DFS；HR=1.27，p值<10⁻³）均显著较差。单因素与多因素分析证实，该基因表达状态是临床预后的独立预测因子（p值<10⁻³，HR=2.18，95%置信区间1.26-3.76），其预测效能优于病理分级（p值<10⁻³，HR=1.2，95%置信区间1.08-1.33）。此外，表面活性物质代谢相关基因分析显示其在低危组表达更高，且与良好预后相关。通过整合多个独立队列（n=779），我们验证了上述发现，并确认CIN表型基因状态可作为肺腺癌的关键预后标志物。基因组特征分析进一步揭示，高危组在KEAP1、LYST、SETD2和TP53等关键基因中存在高频突变，且该组癌基因更易出现拷贝数增加。本研究阐明了CIN表型基因状态作为肺腺癌预后预测指标的重要意义及其与转录组和基因组改变的关联，为后续临床验证和潜在治疗干预奠定了基础。
肿瘤(癌症)患者之家