Volume 35, No 12, Dec 2025

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 35 Issue 12, December 2025: 1037-1055   |  Open Access

ORIGINAL ARTICLES

Genomic and transcriptomic dynamics in the stepwise progression of lung adenocarcinoma

Fangqiu Fu^1,2,3,† , Jun Shang^1,2,3,† , Yueren Yan^1,2,3,† , He Jiang^4,† , Han Han^1,2,3,† , Hui Yuan^1,2,3,† , Zhendong Gao^1,2,3 , Jingcheng Yang⁴ , Jian Gao^5,6 , Jun Wang^5,6 , Yunjian Pan^1,2,3 , Yicong Lin^3,7 , Ting Ye^1,2,3 , Yiliang Zhang^1,2,3 , Yawei Zhang^1,2,3 , Jiaqing Xiang^1,2,3 , Hong Hu^1,2,3 , Zhiwei Cao^5,6 , Yuanting Zheng⁴ , Yuan Li^3,7 , Yang Zhang^1,2,3 , Li Jin^4,* , Leming Shi⁴ , Haiquan Chen^1,2,3

¹Department of Thoracic Surgery and State Key Laboratory of Genetics and Development of Complex Phenotypes, Fudan University Shanghai Cancer Center, Shanghai, China
²Institute of Thoracic Oncology, Fudan University, Shanghai, China
³Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
⁴State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute and Shanghai Cancer Center, Fudan University, Shanghai, China
⁵International Human Phenome Institutes (Shanghai), Shanghai, China
⁶School of Life Sciences, Fudan University, Shanghai, China
⁷Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
^†These authors contributed equally: Fangqiu Fu, Jun Shang, Yueren Yan, He Jiang, Han Han, Hui Yuan
Correspondence: Li Jin(lijin@fudan.edu.cn)

Lung adenocarcinoma (LUAD) progresses from pre-invasive to invasive stages, as well as from ground-glass opacities (GGOs) to solid nodules. However, the dynamic genomic and transcriptomic changes underlying LUAD progression are incompletely understood. Here, we performed whole-genome and transcriptome sequencing on 1008 LUAD samples from 954 patients who underwent surgery at Fudan University Shanghai Cancer Center, with comprehensive follow-up data. There was one atypical adenomatous hyperplasia, 42 adenocarcinomas in situ, 116 minimally invasive adenocarcinomas, and 849 invasive adenocarcinomas spanning all pathological stages. EGFR was the most frequently mutated gene in the study cohort, followed by TP53, RBM10, KRAS, and KMT2D. Mutation frequencies of tumor suppressor genes, such as TP53, RB1, MGA, KEAP1, and STK11, increased as the disease progressed to higher stages. A higher level of genomic instability was seen in LUAD compared with AAH/AIS/MIA samples, characterized by a higher tumor mutation burden, increased somatic copy number alteration burden, and increased structural variation burden. Notably, MAP2K1 E102–I103 deletion was frequently observed in pre-invasive samples, which endowed alveolar type II cells with increased growth potential and initiated tumor formation, suggesting that it is a potential driver mutation of LUAD. In summary, our study highlights key molecular changes during the stepwise progression of LUAD, provides insights into the identification of novel therapeutic targets, and helps to define the curative time window for this disease.

https://doi.org/10.1038/s41422-025-01200-w

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