Resumen
Viral mutations at the preS region of hepatitis B virus (HBV) significantly increase the risk of developing hepatocellular carcinoma (HCC). Compared to HBV preS deletion, the oncogenic effect of preS combo mutation has rarely been investigated. With a cohort including 2114 subjects, we demonstrated that preS combo mutations G2950A/G2951A/A2962G/C2964A and C3116T/T31C significantly increased the risk of HCC in patients without antiviral treatment, whereas preS2 deletion significantly increased the risk of HCC in patients with antiviral treatment. The prevalence of C3116T/T31C (43.61%) was higher than preS2 deletion (7.16%). By using Sleeping Beauty mouse models and in vitro experiments, we found G2950A/G2951A/A2962G/C2964A, C3116T/T31C, and preS2 deletion promoted hepatocarcinogenesis by increasing levels of inflammatory cytokines, activating STAT3 pathway, enhancing endoplasmic reticulum stress, and altering gene expression profiles in inflammation- and metabolism-related pathways. These results suggest that preS combo mutations G2950A/G2951A/A2962G/C2964A and C3116T/T31C had similar oncogenic effects of preS2 deletion and should also be monitored.