AccScience Publishing / EJMO / Online First / DOI: 10.36922/EJMO025220219
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ORIGINAL RESEARCH ARTICLE

Deciphering the co-mutation landscape and clinical implications in SMARCA4-mutant lung adenocarcinoma

Yufeng Li1 ,  Zhipeng Wei2†* ,  Yifan Xu3†*
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1 Department of Oncology, Clinical Medical College, Qingdao University, Qingdao, Shandong, China
2 Department of Ophthalmology, Clinical Medical College, Qingdao University, Qingdao, Shandong, China
3 Department of Rehabilitation Medicine, Clinical Medical College, Qingdao University, Qingdao, Shandong, China
†These authors contributed equally to this work.
EJMO, 025220219 https://doi.org/10.36922/EJMO025220219
Received: 27 May 2025 | Revised: 21 July 2025 | Accepted: 6 August 2025 | Published online: 7 November 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
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Abstract

Introduction: Lung adenocarcinoma (LUAD) exhibits significant genomic heterogeneity, with SMARCA4 mutations often co-occurring with other mutated genes that may shape disease progression and patient outcomes.

Objective: The objective of the study is to investigate the impact of co-mutated genes on the prognosis and immunotherapeutic response in SMARCA4-mutant LUAD.

Methods: Genomic and clinical data from SMARCA4-mutant LUAD patients were extracted from the Memorial Sloan Kettering cohort through cBioPortal, with overall survival (OS) as the primary endpoint. We systematically assessed the most frequent coexisting genomic alterations.

Results: Within a cohort of 5,957 LUAD patients, we identified 8% (n = 477) harboring SMARCA4 mutations. The most frequent co-mutations included TP53 (49%), STK11 (48%), KEAP1 (46%), KRAS (39%), and CDKN2A (33%). TP53 co-mutations exhibited significant mutual exclusivity with STK11, KEAP1, KRAS, and CDKN2A. Multivariable analysis revealed that KRAS, STK11, and KEAP1 co-mutations independently predicted shortened survival, whereas CDKN2A and TP53 co-mutation status showed no significant prognostic impact. Notably, TP53 co-mutations were associated with elevated tumor mutational burden and higher programmed death-ligand 1 expression. In Stage IV SMARCA4-mutant LUAD patients, an improved prognosis associated with co-mutation of TP53 and KRAS was observed with immune checkpoint inhibitor therapy.

Conclusion: In SMARCA4-mutant LUAD patients, TP53, STK11, KEAP1, KRAS, and CDKN2A were the most frequent co-occurring genomic alterations. Multivariable analysis identified KRAS, STK11, and KEAP1 co-mutations as independent adverse prognostic factors. Notably, tumors harboring STK11/KEAP1 double mutations or KRAS/STK11/KEAP1 triple mutations exhibited extremely poor OS, whereas TP53 co-mutations correlated with favorable outcomes and significant immunotherapy benefit. Intriguingly, TP53 mutations demonstrated mutual exclusivity with KRAS, STK11, and KEAP1 alterations, suggesting divergent oncogenic trajectories.

Keywords
SMARCA4
Lung adenocarcinoma
Co-mutation
Immunotherapy
Prognosis
Exclusivity
Funding
None.
Conflict of interest
The authors declare that they have no competing financial interests or personal relationships.
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Eurasian Journal of Medicine and Oncology, Electronic ISSN: 2587-196X Print ISSN: 2587-2400, Published by AccScience Publishing
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