Additional N-glycosylation mutation in the major hydrophilic region of hepatitis B virus S gene is a risk indicator for hepatocellular carcinoma occurrence in patients with coexistence of HBsAg/anti-HBs.

Xiaodong Li,Zhihui Xu,Jin Li,Rongjuan Chen,Yan Qiao,Shumei Lin,Shanshan Lu,Yan Liu,Lanlan Si,Li Zhao,Dongping Xu,Kai Zhang

doi:10.18632/oncotarget.18682

Abstract

The study aimed to determine the association of additional N-glycosylation mutations in the major hydrophilic region (MHR) of hepatitis B virus (HBV) S gene with hepatocellular carcinoma (HCC) occurrence in HBsAg/anti-HBs coexistent patients. A total of 288 HBsAg/anti-HBs coexistent patients and 490 single HBsAg-positive patients were enrolled, including 193 with HCC, 433 with chronic hepatitis B (CHB), and 152 with acute-on-chronic liver failure (ACLF). The HBV S genes were amplified from serum and sequenced. The frequency of additional N-glycosylation mutations was significantly higher in HCC patients (12.37%) than in CHB patients (4.39%) and ACLF patients (2.63%). The frequency escalated by an order of single HBsAg-positive non-HCC (1.61%), single HBsAg-positive HCC (5.98%), HBsAg/anti-HBs coexistent non-HCC (8.01%), and HBsAg/anti-HBs coexistent HCC (22.36%). Twelve kinds of mutations/mutation patterns were detected, five of which have not been reported. Multivariate analysis showed that age > 40 years [OR, 3.005; 95% CI, 1.177−7.674; P = 0.021], alpha-fetoprotein > 10 ng/mL [OR, 4.718; 95% CI, 2.406−9.251; P <0.001], cirrhosis [OR, 6.844; 95% CI, 2.773−16.891, P < 0.001], Hepatitis B e antigen negativity [OR, 2.218; 95% CI, 4.335, P = 0.020], and additional N-glycosylation mutation [OR, 2.831; 95% CI, 1.157−6.929; P = 0.023] were independent risk factors for HCC in HBsAg/anti-HBs coexistent patients. Dynamical analysis showed that the additional N-glycosylation mutations existed 1-4 years prior to HCC occurrence in eight of 18 patients observed. In conclusion, the dditional N-glycosylation mutations together with HBsAg/anti-HBs coexistence might serve as a predictive indicator for HCC occurrence in chronic HBV-infected patients.

Highlights

Hepatitis B virus (HBV) infection is a global pandemic disease that affects two billion people worldwide; up to 80% of hepatocellular carcinomas (HCC) are caused by hepatitis B virus (HBV) infection, and about 300,000 people die of HBV related HCC each year [1, 2]
Of all 778 patients, 106 patients were infected with genotype B HBV and 664 patients were infected with genotype C HBV, 8 patients were infected with other genotype HBV
We found that the frequency of the additional N-glycosylation mutations in the major hydrophilic region (MHR) of HBV S gene was significantly higher in HBsAg/anti-HBs coexistent patients than in single HBsAg-positive patients, suggesting that the additional N-glycosylation mutation may play an important role in the HBsAg/anti-HBs coexistent status

Summary

Introduction

Hepatitis B virus (HBV) infection is a global pandemic disease that affects two billion people worldwide; up to 80% of hepatocellular carcinomas (HCC) are caused by HBV infection, and about 300,000 people die of HBV related HCC each year [1, 2]. Diagnosis through intensive monitoring of populations at risk is critical for the management of HCC and comprehensive knowledge on risk factors associated with HCC occurrence is important. Both host and virus factors are involved in the occurrence of HBV-related HCC, while the knowledge of risk factors is still far from complete. Coexistence of detectable HBsAg and anti-HBs in serum samples has been reported in approximately 5% of patients chronically infected with HBV, [5, 6]. It was suggested that the coexistence of HBsAg and anti-HBs may be related to HCC

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Conclusion