Identification of a DNA Damage Response and Repair-Related Gene-Pair Signature for Prognosis Stratification Analysis in Hepatocellular Carcinoma

Abstract

Background: Nowadays, although the cause of hepatocellular carcinoma (HCC) mortality and recurrence remains at a high level, the 5-year survival rate is still very low. The DNA damage response and repair (DDR) pathway may affect HCC patients’ survival by influencing tumor development and therapeutic response. It is necessary to identify a prognostic DDR-related gene signature to predict the outcome of patients.Methods: Level 3 mRNA expression and clinical information were extracted from the TCGA website. The GSE14520 datasets, ICGC-LIRI datasets, and a Chinese HCC cohort were served as validation sets. Univariate Cox regression analysis and LASSO-penalized Cox regression analysis were performed to construct the DDR-related gene pair (DRGP) signature. Kaplan–Meier survival curves and time-dependent receiver operating characteristic (ROC) analysis curves were calculated to determine the predictive ability of this prognostic model. Then, a prognostic nomogram was established to help clinical management. We investigated the difference in biological processes between HRisk and LRisk by conducting several enrichment analyses. The TIDE algorithm and R package “pRRophetic” were applied to estimate the immunotherapeutic and chemotherapeutic response.Results: We constructed the prognostic signature based on 23 DDR-related gene pairs. The patients in the training datasets were divided into HRisk and LRisk groups at median cut-off. The HRisk group had significantly poorer OS than the LRisk group, and the signature was an independent prognostic indicator in HCC. Furthermore, a nomogram of the riskscore combined with TNM stage was constructed and detected by the calibration curve and decision curve. The LRisk group was associated with higher expression of HBV oncoproteins and metabolism pathways, while DDR-relevant pathways and cell cycle process were enriched in the HRisk group. Moreover, patients in the LRisk group may be more beneficial from immunotherapy. We also found that TP53 gene was more frequently mutated in the HRisk group. As for chemotherapeutic drugs commonly used in HCC, the HRisk group was highly sensitive to 5-fluorouracil, while the LRisk group presented with a significantly higher response to gefitinib and gemcitabine.Conclusion: Overall, we developed a novel DDR-related gene pair signature and nomogram to assist in predicting survival outcomes and clinical treatment of HCC patients. It also helps understand the underlying mechanisms of different DDR patterns in HCC.

DNA Damage Repair Classifier Defines Distinct Groups in Hepatocellular Carcinoma

“…Previous studies have detected similar molecular classes. Most studies emphasized two main groups based on the DNA repair genes’ RNA expression [ 8 , 12 , 13 , 60 ]. Three previous studies identified two DNA repair groups: Oshi et al found low- and high-repair groups based on a gene set that included 150 genes [ 12 ]; Lin et al classified DNA-repair-activated and -suppressed groups using 276 genes [ 13 ]; and Chen et al found low- and high-risk DNA repair groups based on 23 DDR-related gene pairs [ 60 ].…”

“…Most studies emphasized two main groups based on the DNA repair genes’ RNA expression [ 8 , 12 , 13 , 60 ]. Three previous studies identified two DNA repair groups: Oshi et al found low- and high-repair groups based on a gene set that included 150 genes [ 12 ]; Lin et al classified DNA-repair-activated and -suppressed groups using 276 genes [ 13 ]; and Chen et al found low- and high-risk DNA repair groups based on 23 DDR-related gene pairs [ 60 ]. Across these studies, similar to our results, the high-repair-activated samples were associated with worse survival, and these authors further found that high-repair-/DDR-activated samples were associated with distinct immune profiles, poor differentiation, elevated intratumor heterogeneity, and mutation burden.…”

The DNA damage repair-related lncRNAs signature predicts the prognosis and immunotherapy response in gastric cancer

“…Numerous studies have demonstrated the crucial role of the DDR process in regulating the biological behavior and therapeutic susceptibility of tumor cells (69). Risk models based on DDRrelated genes have been constructed for different cancers, such as lung adenocarcinoma (LUAD), hepatocellular carcinoma (HCC), and soft tissue sarcoma, with many studies focusing exclusively on the prognostic value of the models (70)(71)(72). However, DDR-related lncRNAs have received less attention in GC research.…”

Significance of Pre-Treatment CALLY Score Combined with EBV-DNA Levels for Prognostication in Non-Metastatic Nasopharyngeal Cancer Patients: A Clinical Perspective

“… 4 Apart form TNM stage, the pre-EBV DNA, reflecting tumor burden, has emerged as a significant factor in the clinical diagnosis, risk classification, dynamic monitoring, and prognosis of NPC patients, serving as an important a supplement for the TNM staging system. 20 , 21 Patients with higher pre-EBV DNA copy numbers appear to have a greater risk of distant metastasis, necessitating more aggressive treatment. Nevertheless, these considerations often overlook the impact of hematological parameters on the treatment of NPC patients, potentially affecting treatment outcomes.…”