Genomic and transcriptomic dynamics in the stepwise progression of lung adenocarcinoma

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.

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Publication Details

Journal
Cell Research
Published
2025-12-04
DOI
https://doi.org/10.1038/s41422-025-01200-w
Citations
2
Primary Topic
Lung Cancer Treatments and Mutations
Type
article
Field-Weighted Citation Impact
3.04

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article

Genomic and transcriptomic dynamics in the stepwise progression of lung adenocarcinoma

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2 citations
Cell Research
Lung Cancer Treatments and Mutations
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article

Genomic and transcriptomic dynamics in the stepwise progression of lung adenocarcinoma

Hong Hu, Hui Yuan, Yuanting Zheng, Zhendong Gao, Leming Shi, Jiaqing Xiang, Jingcheng Yang, Yiliang Zhang, Yicong Lin, Fangqiu Fu, Yuan Li, Jun Shang, Yueren Yan, Jian Gao, Yunjian Pan, Ting Ye, Han Han, Yang Zhang, Jun Wang, Jin Li, Haiquan Chen, He Jiang, Zhiwei Cao, Yawei Zhang
article en
2 citations

Abstract

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.

Cell ResearchVol. 35(12)
Shanghai Medical College of Fudan University (CN), Fudan University (CN), Fudan University Shanghai Cancer Center (CN), State Key Laboratory of Genetic Engineering
Shanghai Municipal Health Commission, National Natural Science Foundation of China
Openalex Percentile: Top 7%
Lung Cancer Treatments and Mutations
3.04
DOIOpen Access PDFOpenAlex
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