Sex Hormone Receptors, HBV Integrations and Their Prognostic Predictive Value Among Hepatocellular Carcinoma Patients

Hepatocellular carcinoma (HCC) related to hepatitis B virus (HBV) infection predominantly affects males, yet few studies have investigated the association between sex hormones and HBV integrations, and their involvement in HCC prognosis. We assessed estrogen receptor alpha (ERα) and androgen receptor (AR) expression via immunohistochemistry on tissue microarrays constructed from 426 HBV-related HCC samples. HBV integration features were determined using HBV-captured sequencing data. Logistic regression models were utilized to evaluate the association between sex hormone receptor expression level and HBV integration features. Cox regression models, combined with machine learning (ML) methods, were implemented to investigate the prognostic value of sex hormone receptors and HBV integrations concerning overall survival. We found high AR expression level was significantly associated with higher HBV integration levels (adjusted odds ratio [aOR] = 1.84, 95% confidence interval [CI]: 1.09-3.11, P for trend = 0.012), TERT integration (aOR = 2.34, 95% CI: 1.16-4.74, P for trend = 0.047), intergenic integration (aOR = 2.25, 95% CI: 1.20-4.24, P for trend = 0.021), and promoter integration (aOR = 1.81, 95% CI: 1.00-3.31, P for trend = 0.034). The inclusion of sex hormone receptors and HBV integrations in the predictive models led to improvements across all performance metrics in the Cox regression analyses (AUC improvement: 0.014 [Training], 0.026 [Validation]) and the ML (AUC improvement: 0.022 [Training]), although a slight deterioration in performance was noted in the ML validation set. The results suggested a relationship between AR expression level and HBV integration events, as well as the potential utility of HBV integration biomarkers and sex hormone receptor profiles in assessing post-surgical prognosis among HCC patients.