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ORIGINAL RESEARCH ARTICLE

Genomic alterations of homologous recombination deficiency in Chinese NSCLC patients

Shuang Xiang1 ,  Changqiong Shen2 ,  Chun Huang3 ,  Ya-ting Yang1 ,  Jing Guo4 ,  Yi Liu5 ,  Mingzhu Yin1* ,  Song Duan1*
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1 Department of Pathology, Chongqing University Three Gorges Hospital, Chongqing, China
2 Department of Radiology, People’s Hospital Affiliated to Chongqing Three Gorges Medical College, Chongqing, China
3 Department of Respiratory Medicine, Chongqing University Three Gorges Hospital, Chongqing, China
4 Department of Oncology, Chongqing University Three Gorges Hospital, Chongqing, China
5 Department of Thoracic Surgery, Chongqing University Three Gorges Hospital, Chongqing, China
Tumor Discovery, 025180032 https://doi.org/10.36922/TD025180032
Received: 30 April 2025 | Revised: 20 May 2025 | Accepted: 21 May 2025 | Published online: 6 June 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Homologous recombination deficiency (HRD) affects genomic stability and has potential as a biomarker for the effectiveness of poly (ADP-ribose) polymerase (PARP) inhibitors and immune checkpoint inhibitors. However, the clinical and molecular profile of HRD in non-small cell lung cancer (NSCLC), particularly in the Chinese population, remains poorly characterized. Based on the next-generation sequencing data of 158 Chinese NSCLC patients, we analyzed the HRD scores of mutations in homologous recombination repair (HRR) genes and dissected the correlation between HRD state and programmed death-ligand 1 (PD-L1) expression. Alterations in HRR genes were observed in 8.9% of the patients, with ATM and BRCA2 being the most commonly affected genes. HRD-high (HRD-H) status was significantly associated with advanced disease stage (≥III) and lung squamous cell carcinoma (LUSC). Transcriptomic analysis revealed distinct gene expression profiles between HRD-H and HRD-low (HRD-L) subgroups, with HRD-H tumors exhibiting predominantly downregulated genes. While EGFR mutations occurred at similar frequencies across HRD status, TP53 mutations were significantly enriched in HRD-H cases. HRD-H status correlated with higher PD-L1 positivity in NSCLC overall, but not within the lung adenocarcinoma (LUAD) subgroup in our cohort. The Cancer genome atlas analysis showed higher PD-L1 protein expression in HRD-H LUAD, but not in LUSC. Kyoto Encyclopedia of Genes and Genomes analysis identified enrichment of complement and coagulation cascades, ABC transporters, and bile secretion pathways in HRD-H tumors, suggesting links to immune evasion and drug resistance. This study elucidates the genomic landscape of HRD in Chinese NSCLC patients and provides insights into its potential clinical utility for therapeutic targeting. Our findings suggest that integrated HRD scoring may guide the application of PARP inhibitors and immunotherapy in specific NSCLC patient subgroups. Further prospective clinical studies are needed to validate the predictive value of HRD scoring in NSCLC treatment and to optimize patient selection strategies.

Graphical abstract
Keywords
Homologous recombination deficiency
Immunotherapy biomarkers
Next-generation sequencing
Non-small cell lung cancer
Programmed death-ligand 1
Funding
This study was jointly funded by the Wanzhou District Science and Technology Bureau of Chongqing (Grant No.: wzstc-kw2022029) and the Wanzhou District Health Commission of Chongqing (Grant No. wzstc-kw2022029).
Conflict of interest
Mingzhu Yin is an Editor-in-Chief of this journal but was not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
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Tumor Discovery, Electronic ISSN: 2810-9775 Print ISSN: 3060-8597, Published by AccScience Publishing
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