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Background <p>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.</p> Methods <p>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 (<a href="http://www.cbioportal.org">www.cbioportal.org</a>). 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−&#xa0;group using log-rank testing (<i>p</i> = 0.034). Univariate and multivariate Cox analyses were performed to establish prognostic value.</p> Results <p>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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月5日

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  • Bin Ye,
  • Chunzhi Wu,
  • Xiaoying Quan,
  • Xiaoli Jia,
  • Lin Yao,
  • Lei Lei,
  • Xiaoyan Chen

摘要

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.