Identification of DNA repair gene signature and potential molecular subtypes in hepatocellular carcinoma

Abstract

DNA repair is a critical factor in tumor progression as it impacts tumor mutational burden, genome stability, PD-L1 expression, immunotherapy response, and tumor-infiltrating lymphocytes (TILs). In this study, we present a prognostic model for hepatocellular carcinoma (HCC) that utilizes genes related to the DNA damage response (DDR). Patients were stratified based on their risk score, and groups with lower risk scores demonstrated better survival rates compared to those with higher risk scores. The prognostic model’s accuracy in predicting 1-, 3-, and 5-year survival rates for HCC patients was analyzed using receiver operator curve analysis (ROC). Results showed good accuracy in predicting survival rates. Additionally, we evaluated the prognostic model’s potential as an independent factor for HCC prognosis, along with tumor stage. Furthermore, nomogram was employed to determine the overall survival year of patients with HCC based on this independent factor. Gene set enrichment analysis (GSEA) revealed that in the high-risk group, apoptosis, cell cycle, MAPK, mTOR, and WNT cascades were highly enriched. We used training and validation datasets to identify potential molecular subtypes of HCC based on the expression of DDR genes. The two subtypes differed in terms of checkpoint receptors for immunity and immune cell filtration capacity.Collectively, our study identified potential biomarkers of HCC prognosis, providing novel insights into the molecular mechanisms underlying HCC.

Research advances in immunotherapy combined with DNA damage response inhibitors for liver cancer therapy

“…Different susceptibility variants associated with different risk factors may occur in different populations [19] . The presence of common mutations in the homologous recombination repair and mismatch repair (HRR-MMR) or HRR and base excision repair (HRR-BER) pathways in the DDR pathway has been associated with high tumor mutational burden (TMB), neoantigen load (NAL), and immune regulatory gene expression [88,89] , and mismatch repair defects (MMR-D), homologous recombination mutations, and repair gene mutations in the pole mutation pathway are associated with increased expression of the cytotoxicity-related genes PD-1 and PD-L1 as well as elevated NAL, CD4+ and CD8+ TILs [90] . DDRassociated genes are potential predictors of treatment with ICIs.…”