DNA damage repair-related gene signature can influence immune status and predict prognosis in hepatocellular carcinoma

Abstract

Abstract Background The heterogeneity of hepatocellular carcinoma (HCC) poses a challenge for accurate prognosis prediction. DNA damage repair genes (DDRGs) have an impact on a wide range of malignancies. However, the relevance of these genes in HCC prognosis has received little attention. In this study, we want to develop a prognostic signature that will open up novel therapy options for HCC. Methods We acquired mRNA expression profiles and clinical data of HCC patients from the Cancer Genome Atlas (TCGA) database. A polygenic prognostic model for HCC was constructed using selection operator Cox analysis and least absolute shrinkage. The model was validated using the International Cancer Genome Consortium (ICGC) database. Overall survival (OS) between high-risk and low-risk groups was compared using Kaplan-Meier analysis. Independent predictors of OS were identified through both univariate and multivariate Cox analyses. To determine immune cell infiltration scores and activity in immune-related pathways, a single-sample gene set enrichment analysis was performed. Protein expression levels of prognostic genes were compared using immunohistochemistry between HCC tissue and normal liver tissue. Results A DDRGs signature model was developed using LASSO Cox regression analysis. Patients in the high-risk group had worse overall survival compared to the low-risk group. Receiver operating characteristic curve analysis confirmed the prognostic gene’s predictive ability. Multivariate Cox analysis showed that the risk score is an independent predictor of OS. Functional analysis revealed a strong association with cell cycle and antigen binding pathways, and the risk score was highly correlated with tumor grade, tumor stage, and types of immune infiltrate. High expression levels of prognostic genes were significantly correlated with increased sensitivity of cancer cells to anti-tumor drugs. Immunohistochemistry staining indicated that, except for NEIL3, the other 9 genes were highly expressed in HCC and expressed in normal liver tissue, consistent with our bioinformatic analysis. Conclusion Ten DDRGs were utilized to create a new signature that might influence the immunological state in HCC and be used for prognostic prediction. In addition, blocking these genes could be an alternate treatment.