DNA replication stress stratifies prognosis and enables exploitable therapeutic vulnerabilities of HBV-associated hepatocellular carcinoma: an in silico strategy towards precision oncology

Background Hepatitis B virus (HBV), the main risk factor for hepatocellular carcinoma (HCC) development, integrates into the host genome, causing genetic instability, which may trigger malignancies to exhibit chronic DNA replication stress, providing exploitable therapeutic vulnerabilities. Therefore, customizing prognostication approach and expanding therapeutic options are of great clinical significance to HBV-associated HCCs. Methods A robust machine-learning framework was designed to develop a DNA replication stress-related prognostic index ( PI RS ) based on 606 retrospectively collected HBV-associated HCC cases. Molecular profiles and drug response of HCC cell lines were leveraged to predict therapeutic targets and agents for patients with high mortality risk. Results Compared with established population-based predictors, PI RS manifested superior performance for prognostic prediction in HBV-associated HCCs. Lower PI RS tightly associated with higher expression of HBV oncoproteins, activated immune/metabolism pathways and higher likelihood of responding to immunotherapy; while higher PI RS showed co-occurrence manner with elevated Ki-67 progression marker and cancer stemness, and significantly enriched in DNA replication stress, cell cycle pathways, chromatin remodeling regulons, and presented an ‘immune-cold’ phenotype with unfavorable clinical outcome. Through large-scale in silico drug screening, four potential therapeutic targets ( TOP2A, PRMT1, CSNK1D , and PPIH ) and five agents including three topoisomerase inhibitors (teniposide, doxorubicin, and epirubicin) and two CDK inhibitors (JNJ-7706621 and PHA-793887) were identified for patients with high PI RS . Conclusions Overall, PI RS holds potential to improve the population-based therapeutic strategies in HCC and sheds new insight to the clinical management for those HBV carriers; current analytic framework provides a roadmap for the rational clinical development of personalized treatment. ### Competing Interest Statement The authors have declared no competing interest.