Liu Bing, Tao Wei, Zhou Xuantong, Xu Li-Di, Luo Yanrui, Yang Xin, Min Qingjie, Huang Miao, Zhu Yuge, Cui Xinrun, Wang Yaqi, Gong Tongyang, Zhang Enli, Huang Yu S, Chen Weizhi, Yan Shi, Wu Nan
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery II, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
Genecast Biotechnology Co, Ltd, Wuxi, Jiangsu, China.
Mol Cancer. 2025 May 1;24(1):129. doi: 10.1186/s12943-025-02333-7.
Early-stage poorly differentiated lung adenocarcinoma (LUAD) is plagued by a high risk of postoperative recurrence, and its prognostic heterogeneity complicates treatment and surveillance planning. We conducted this integrative multi-omics study to identify those patients with a truly high risk of adverse outcomes.
Whole-exome, RNA and whole methylome sequencing were carried out on 101 treatment-naïve early-stage poorly differentiated LUADs. Integrated analyses were conducted to disclose molecular characteristics and explore molecular subtyping. Functional validation of key molecules was carried out through in vitro and in vivo experiments.
Recurrent tumors exhibited significantly higher ploidy (p = 0.024), the fraction of the genome altered (FGA, p = 0.042), and aneuploidy (p < 0.05) compared to non-recurrent tumors, as well as a higher frequency of CNVs. Additionally, recurrent tumors showed hypomethylation at both the global level and in CpG island regions. Integrative transcriptomic and methylation analyses identified three molecular subtypes (C1, C2, and C3), with the C1 subtype presenting the worst prognosis (p = 0.024). Although frequently mutated genes showed similar mutation frequencies across the three subtypes, the C1 subtype exhibited the highest tumor mutation burden (TMB), mutant-allele tumor heterogeneity (MATH), aneuploidy, and HLA loss of heterozygosity (HLA-LOH), along with relatively lower immune cell infiltration. Furthermore, GINS1 and CPT1C were found to promote LUAD progression, and their high expression correlated with a poor prognosis.
This multi-omics study identified three integrative subtypes with distinct prognostic implications, paving the way for more precise management and postoperative monitoring of early-stage poorly differentiated LUAD.
早期低分化肺腺癌（LUAD）术后复发风险高，其预后异质性使治疗和监测计划复杂化。我们开展了这项综合多组学研究，以识别那些真正具有不良预后高风险的患者。
对101例未经治疗的早期低分化LUAD进行全外显子组、RNA和全甲基化组测序。进行综合分析以揭示分子特征并探索分子亚型。通过体外和体内实验对关键分子进行功能验证。
与非复发性肿瘤相比，复发性肿瘤显示出明显更高的倍性（p = 0.024）、基因组改变分数（FGA，p = 0.042）和非整倍体（p < 0.05），以及更高的CNV频率。此外，复发性肿瘤在整体水平和CpG岛区域均表现为低甲基化。综合转录组学和甲基化分析确定了三种分子亚型（C1、C2和C3），其中C1亚型预后最差（p = 0.024）。尽管三个亚型中常见突变基因的突变频率相似，但C1亚型表现出最高的肿瘤突变负荷（TMB）、突变等位基因肿瘤异质性（MATH）、非整倍体和HLA杂合性缺失（HLA-LOH），同时免疫细胞浸润相对较低。此外，发现GINS1和CPT1C促进LUAD进展，它们的高表达与不良预后相关。
这项多组学研究确定了三种具有不同预后意义的综合亚型，为早期低分化LUAD的更精确管理和术后监测铺平了道路。
