Multi‑omics analysis identifies different molecular subtypes with unique outcomes in early-stage poorly differentiated lung adenocarcinoma
Abstract Introduction 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...
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BMC
2025-05-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-025-02333-7 |
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| author | Bing Liu Wei Tao Xuantong Zhou Li-Di Xu Yanrui Luo Xin Yang Qingjie Min Miao Huang Yuge Zhu Xinrun Cui Yaqi Wang Tongyang Gong Enli Zhang Yu S. Huang Weizhi Chen Shi Yan Nan Wu |
| author_facet | Bing Liu Wei Tao Xuantong Zhou Li-Di Xu Yanrui Luo Xin Yang Qingjie Min Miao Huang Yuge Zhu Xinrun Cui Yaqi Wang Tongyang Gong Enli Zhang Yu S. Huang Weizhi Chen Shi Yan Nan Wu |
| author_sort | Bing Liu |
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| description | Abstract Introduction 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. Methods 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. Results 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. Conclusions 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. |
| format | Article |
| id | doaj-art-63c311da23f34d01bb8ce2a3f28bcb25 |
| institution | OA Journals |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| series | Molecular Cancer |
| spelling | doaj-art-63c311da23f34d01bb8ce2a3f28bcb252025-08-20T01:47:33ZengBMCMolecular Cancer1476-45982025-05-0124112410.1186/s12943-025-02333-7Multi‑omics analysis identifies different molecular subtypes with unique outcomes in early-stage poorly differentiated lung adenocarcinomaBing Liu0Wei Tao1Xuantong Zhou2Li-Di Xu3Yanrui Luo4Xin Yang5Qingjie Min6Miao Huang7Yuge Zhu8Xinrun Cui9Yaqi Wang10Tongyang Gong11Enli Zhang12Yu S. Huang13Weizhi Chen14Shi Yan15Nan Wu16Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery II, Peking University Cancer Hospital & InstituteGenecast Biotechnology Co, LtdKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery II, Peking University Cancer Hospital & InstituteGenecast Biotechnology Co, LtdGenecast Biotechnology Co, LtdKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Molecular Oncology, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery II, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery II, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery II, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery II, Peking University Cancer Hospital & InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery II, Peking University Cancer Hospital & InstituteGenecast Biotechnology Co, LtdGenecast Biotechnology Co, LtdGenecast Biotechnology Co, LtdKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery II, Peking University Cancer Hospital & InstituteState Key Laboratory of Molecular Oncology, Frontiers Science Center for Cancer Integrative Omics, Department of Thoracic Surgery II, Beijing Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & InstituteAbstract Introduction 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. Methods 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. Results 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. Conclusions 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.https://doi.org/10.1186/s12943-025-02333-7Multi-omicsPoorly differentiatedLung adenocarcinoma |
| spellingShingle | Bing Liu Wei Tao Xuantong Zhou Li-Di Xu Yanrui Luo Xin Yang Qingjie Min Miao Huang Yuge Zhu Xinrun Cui Yaqi Wang Tongyang Gong Enli Zhang Yu S. Huang Weizhi Chen Shi Yan Nan Wu Multi‑omics analysis identifies different molecular subtypes with unique outcomes in early-stage poorly differentiated lung adenocarcinoma Molecular Cancer Multi-omics Poorly differentiated Lung adenocarcinoma |
| title | Multi‑omics analysis identifies different molecular subtypes with unique outcomes in early-stage poorly differentiated lung adenocarcinoma |
| title_full | Multi‑omics analysis identifies different molecular subtypes with unique outcomes in early-stage poorly differentiated lung adenocarcinoma |
| title_fullStr | Multi‑omics analysis identifies different molecular subtypes with unique outcomes in early-stage poorly differentiated lung adenocarcinoma |
| title_full_unstemmed | Multi‑omics analysis identifies different molecular subtypes with unique outcomes in early-stage poorly differentiated lung adenocarcinoma |
| title_short | Multi‑omics analysis identifies different molecular subtypes with unique outcomes in early-stage poorly differentiated lung adenocarcinoma |
| title_sort | multi omics analysis identifies different molecular subtypes with unique outcomes in early stage poorly differentiated lung adenocarcinoma |
| topic | Multi-omics Poorly differentiated Lung adenocarcinoma |
| url | https://doi.org/10.1186/s12943-025-02333-7 |
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