The frequency of core MMR gene alterations in lung cancer and their clinical characterization: A comprehensive study of over 26,000 cases

Li Hu; Yuquan Pei; Xiaofeng Wang; Qian Liu; Wenli Cao; Yanfei Liu; Furong Kou; Xingyu Liao; Yaxin Zhang; Jinqiu Rui; Junjie Tang; Shenglei Li; Yang Wang

doi:10.59717/j.xinn-med.2025.100163

The Innovation Medicine > 2025 Vol. 3 > No. 4 > 100163

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The frequency of core MMR gene alterations in lung cancer and their clinical characterization: A comprehensive study of over 26,000 cases

1.
Comprehensive Clinical Trial Ward, Peking University Cancer Hospital & Institute, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing 100142, China
2.
Familial & Hereditary Cancer Center, Peking University Cancer Hospital & Institute, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing 100142, China
3.
Thoracic Surgery II, Peking University Cancer Hospital & Institute, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing 100142, China
4.
Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
5.
Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
6.
Department of Medicine, Geneplus-Beijing, Beijing 102206, China
7.
Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
8.
These authors contributed equally

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Corresponding authors: lishenglei@zzu.edu.cn (S. L.); wangyang@bjmu.edu.cn (Y. W.)
Received Date: July 01, 2025

Accepted Date: October 23, 2025

Published Online: October 31, 2025

The Innovation Medicine 3(4), https://doi.org/10.59717/j.xinn-med.2025.100163 | Cite this article

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PUBLIC SUMMARY
1. Core mismatch repair (cMMR) gene alterations are rare in lung cancer (~1%).
  
  Only ~20% of cMMR gene alterations lead to functional mismatch repair deficiency.
  
  cMMR gene alterations increase tumor mutation burden but not immune cell infiltration.
  
  No additional immunotherapy benefit was observed in limited cases with cMMR gene alterations.

ABSTRACT

ABSTRACT

Mismatch repair (MMR) deficiency is a pan-cancer biomarker predictive of immune checkpoint inhibitor (ICI) response, yet its role in lung cancer remains unclear. We analyzed genomic and clinical data of 26,043 lung cancers (20,997 discovery; 5,046 validation) to comprehensively characterize deleterious core MMR gene alterations and their functional and clinical implications. Deleterious core MMR (cMMR) gene alterations were identified in 0.9% and 1.2% patients of the discovery and validation cohort, respectively, with significant enrichment in squamous carcinomas. Functionally, approximately 20% of tumors with cMMR gene alteration exhibited MMR protein loss and/or microsatellite instability-high, which were nearly absent in cMMR wild-type tumors. The tumors with cMMR gene alteration had a higher rate of tumor mutation burden-high compared to their wild-type counterparts (discovery cohort: 73.6% vs. 39.0%, P<0.001; validation cohort: 55.2% vs. 22.9%; P<0.001). Within a limited subset of advanced lung cancer patients receiving ICIs, response rates and survival outcomes were comparable between cMMR gene alteration and wild-type groups. Immune profiling revealed no significant differences in PD-L1 expression or immune infiltration scores between cMMR gene alteration and wild-type tumors. In summary, cMMR gene alterations are rare in lung cancer but confer genomic instability in a subset of cases. Crucially, the majority of these alterations do not lead to functional MMR deficiency or immune microenvironment activation. These findings indicate that cMMR gene alterations alone may be insufficient to guide immunotherapy decisions. Further studies are warranted to clarify the clinical utility of MMR deficiency in lung cancer.

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Hu L., Pei Y., Wang X., et al. (2025). The frequency of core MMR gene alterations in lung cancer and their clinical characterization: A comprehensive study of over 26,000 cases. The Innovation Medicine 3:100163. https://doi.org/10.59717/j.xinn-med.2025.100163

Hu L., Pei Y., Wang X., et al. (2025). The frequency of core MMR gene alterations in lung cancer and their clinical characterization: A comprehensive study of over 26,000 cases. The Innovation Medicine 3:100163. https://doi.org/10.59717/j.xinn-med.2025.100163

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The frequency of core MMR gene alterations in lung cancer and their clinical characterization: A comprehensive study of over 26,000 cases

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The frequency of core MMR gene alterations in lung cancer and their clinical characterization: A comprehensive study of over 26,000 cases

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