DNA damage response genes in lung cancer: Diagnostic, prognostic, and therapeutic implications - A narrative review

Lung cancer management remains constrained by a fragmented understanding of the clinical implications of DNA Damage Response (DDR) pathways. This review synthesizes current evidence to position DDR variants as potential prognostic, predictive, and therapeutic biomarkers. Prognostically, overexpression of FEN1, BRCA1, and XRCC4/5/6 correlates with poor survival in non-small cell lung cancer, whereas low ERCC1 expression and specific EXO1 or RPA polymorphisms are associated with enhanced responsiveness to platinum-based chemotherapy. As well, deleterious variants in ATM, ERCC family genes, and mismatch repair genes (MSH2, PMS2) may support the identification of patients more likely to benefit from immune checkpoint inhibitors, driven by increased tumor mutational burden and neoantigen load. Therapeutically, synthetic lethality of PARP and ATR inhibitors may offer an opportunity in difficult-to-treat subsets progressing on standard targeted therapies. However, clinical implementation of DDR-related findings faces significant technical limitations regarding testing variability, geographic biases toward Asian populations, and overlapping toxicities in combination trials. To facilitate their integration into routine practice, future research must prioritize assay standardization, broader ethnic representation, and mechanistic exploration of DDR-mediated effects in tumor biology. Integrating these complex molecular interactions is essential to bridge the gap between biological activity and personalized clinical application in lung cancer.