Research Papers:

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

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

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Oncotarget. 2017; 8:61719-61730. https://doi.org/10.18632/oncotarget.18682

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Yan Qiao1,2,*, Shanshan Lu1,*, Zhihui Xu1,*, Xiaodong Li1, Kai Zhang1,4,Yan Liu1, Li Zhao1, Rongjuan Chen1, Lanlan Si1, Shumei Lin4, Dongping Xu1,2 and Jin Li1,3

1Research Center for Clinical and Translational Medicine/Institute of Infectious Diseases, Beijing 302 Hospital, Beijing 100039, China

2Clinical Medical School, Guilin Medical University, Guilin 541004, China

3Medical Department, Beijing 302 Hospital, Beijing 100039, China

4Department of Infectious Disease, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China

*These authors have contributed equally to this work

Correspondence to:

Dongping Xu, email: [email protected]

Jin Li, email: [email protected]

Keywords: hepatitis B virus, mutation, additional N-glycosylation, HBsAg/anti-HBs coexistence, hepatocellular carcinoma

Received: December 22, 2016    Accepted: May 08, 2017    Published: June 27, 2017


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.

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