Genomic alterations of homologous recombination deficiency in Chinese NSCLC patients

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.