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Review | Open Access

The Genomic Evolution of Early‐Stage Non‐Small Cell Lung Cancer

Huatao Tang1,2,3, Yang Zhang1,2,3( ), Haiquan Chen1,2,3 ( )
Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China
Institute of Thoracic Oncology, Fudan University, Shanghai, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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Abstract

The widespread application of low‐dose computed tomography has significantly increased the detection of early‐stage non‐small cell lung cancer (NSCLC); however, therapeutic advances remain limited by an incomplete understanding of the genomic factors underlying tumor evolution. Here, we provide a comprehensive review of the genomic evolution of early‐stage NSCLC, with a particular focus on lung adenocarcinoma and squamous cell carcinoma. We summarize the genomic mechanisms driving pathological progression from pre‐invasive to invasive lesions as well as the molecular alterations associated with radiological progression. Furthermore, we discuss clonal evolution models, highlighting the distinct roles of clonal versus sub‐clonal mutations and the dynamic changes in the tumor microenvironment. Finally, we address the translational implications of these findings for developing novel biomarkers and screening strategies, and outline current methodological limitations and future directions in the field.

Graphical Abstract

This study provides a comprehensive overview of the genomic landscape of early‐stage non‐small cell lung cancer, identifying the 4q12 deletion as a potential exclusive biomarker for the “oncogenic switch” from pre‐invasive to invasive lesions. It delineates that while EGFR and TP53 mutations act as early truncal drivers, the progressive increase in genomic complexity and sub‐clonal diversity facilitates pathological and radiological advancement. These findings offer a molecular framework to refine pulmonary nodule risk stratification, potentially reducing overtreatment and optimizing lung cancer screening strategies.

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Medicine Advances
Pages 1-9

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Cite this article:
Tang H, Zhang Y, Chen H. The Genomic Evolution of Early‐Stage Non‐Small Cell Lung Cancer. Medicine Advances, 2026, 4(1): 1-9. https://doi.org/10.1002/med4.70062

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Received: 06 May 2025
Revised: 15 October 2025
Accepted: 01 December 2025
Published: 08 March 2026
© 2026 The Author(s). Tsinghua University Press.

This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.