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. 2026 Jan 5;17(1):7.
doi: 10.1007/s12672-025-03775-7.

The value of DNA repair gene and TP53 co-mutation in predicting the response of non-small cell lung cancer to immunotherapy

Bin Ye #  1 , Chunzhi Wu #  2 , Xiaoying Quan  2 , Xiaoli Jia  2 , Lin Yao  3 , Lei Lei  2 , Xiaoyan Chen  2
Affiliations

The value of DNA repair gene and TP53 co-mutation in predicting the response of non-small cell lung cancer to immunotherapy

Bin Ye et al. Discov Oncol. .

Abstract

Background: While mutations in DNA repair gene (DDR) or TP53 alone have been linked to favorable outcomes in immunotherapy, their co-mutations may not have the same effect. The co-occurrence of DDR and TP53 mutations may actually impair DNA repair, cause more genomic instability, and worsen prognosis, indicating that they may have a context-specific effect.

Methods: Clinical characteristics and next-generation sequencing (NGS) data of non-small-cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs) were collected from cBioPortal ( www.cbioportal.org ). The incidence of DDR mutations was calculated. Kaplan-Meier analyses were performed to determine overall survival (OS) for the DDR+/TP53+ group vs. the DDR+/TP53- group using log-rank testing (p = 0.034). Univariate and multivariate Cox analyses were performed to establish prognostic value.

Results: Of the 350 patients studied, 78.6% had DDR mutations, 62% had TP53 mutations. The presence of DDR mutation status demonstrated a significant association with tumor mutational burden (TMB). Patients with DDR+/TP53+ mutations had shorter OS outcomes than DDR+/TP53-. Multivariable analysis confirmed that the presence of co-mutations was an independent predictor of poor outcome and diminished ICI efficacy.

Conclusion: While previous reports would suggest that the mutation status of DDR or TP53 leads to a benefit, our results demonstrate that upon co-mutations of DDR/TP53, mutant patients have inferior outcomes in NSCLC for immunotherapy treatments. This signifies that co-mutation status is an important consideration in biomarker-driven treatment strategies.

Keywords: Co-mutation; DNA repair gene; Immunotherapy; NSCLC; TP53.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This was a study undertaken in compliance with the Declaration of Helsinki. The study was approved by the Sixth People’s Hospital of Chengdu [Number (No):2022-k (Research Project)-001]. Written informed consent was obtained from all individuals included in this study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
A violin diagram shows the difference in TMB between patients with different gene mutations. A Only the TP53 gene was mutated, while other DDR genes remained wild type; B DDR gene (including TP53) was wild-type; C TP53 gene is co-mutated with other DDR genes; D TP53 was wild-type, but at least one other DDR gene was mutated. (ns p > 0.05, * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001, **** p ≤ 0.0001)
Fig. 2
Fig. 2
Kaplan–Meier survival analysis of OS based on DDR and TP53 mutation status. A Only the TP53 gene was mutated; B DDR gene (including TP53) was wild-type; C TP53 gene is co-mutated with other DDR genes; D TP53 was wild-type, but at least one other DDR gene was mutated The log-rank test (p = 0.034) showed significantly shorter OS in DDR+/TP53+ patients compared with DDR+/TP53– patients. A risk table with the number of patients at each time point and the median OS values for each group is displayed beneath the curves
See this image and copyright information in PMC

References

    1. Gourzoulidis G, Zisimopoulou O, Boubouchairopoulou N, Michailidi C, Lowry C, Tzanetakos C, et al. Cost-effectiveness analysis of lorlatinib in patients previously treated with anaplastic lymphoma kinase inhibitors for non-small cell lung cancer in Greece. J Health Econ Outcomes Res. 2022;9(1):50–7. 10.36469/jheor.2022.32983. - PMC - PubMed
    1. Qian XJ, Wang JW, Liu JB, Yu X. The mediating role of miR-451/ETV4/MMP13 signalling axis on epithelial-mesenchymal transition in promoting non-small cell lung cancer progression. Curr Mol Pharmacol. 2024;17:e210723218988. 10.2174/1874467217666230721123554. - PubMed
    1. Ullah A, Razzaq A, Alfaifi MY, Elbehairi SEI, Menaa F, Ullah N, et al. Sanguinarine attenuates lung cancer progression via oxidative stress-induced cell apoptosis. Curr Mol Pharmacol. 2024;17:e18761429269383. 10.2174/0118761429269383231119062233. - PubMed
    1. Cai Y, Sheng Z, Dong Z, Wang J. EGFR inhibitor CL-387785 suppresses the progression of lung adenocarcinoma. Curr Mol Pharmacol. 2023;16(2):211–6. 10.2174/1874467215666220329212300. - PubMed
    1. Chen Y, Gao M, Huang Z, Yu J, Meng X. SBRT combined with PD-1/PD-L1 inhibitors in NSCLC treatment: a focus on the mechanisms, advances, and future challenges. J Hematol Oncol. 2020;13(1):105. 10.1186/s13045-020-00940-z. - PMC - PubMed

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