Potential Susceptibility Mutations in C Gene for Hepatitis B-Related Hepatocellular Carcinoma Identified by a Two-Stage Study in Qidong, China.

Lishuai Qu,Cuihua Lu,Taoyang Chen,Xizhong Shen,Jinxia Liu,Zhengpin Ni,Taotao Liu,Haifeng Zhang

doi:10.3390/ijms17101708

Abstract

A two stage study was conducted to explore new potential mutations in the full genome of hepatitis B virus (HBV) on the progression of hepatocellular carcinoma (HCC) in Qidong, China. In stage 1, full genomes of HBV were compared between 30 HCC cases and 30 controls. In stage 2, an independent case–control study including 100 HCC cases and 100 controls was enrolled to verify the relationship between hot-spot mutations and HCC development. Furthermore, a longitudinal study was conducted on 11 HCC cases with serial serum samples available before HCC diagnosis. A total of 10 mutations (including pre-S2 start codon mutation and pre-S deletion in pre-S gene, G1613A, C1653T, A1762T, and G1764A mutations in X gene, A2159G, A2189Y, G2203W, and C2288R mutations in C gene) showed an increased risk of HCC. In the validation study, pre-S deletion, C1653T, A1762T/G1764A, A2159G, A2189Y, G2203W, and C2288R mutations were associated with increased HCC risk in univariate analysis. Multivariate analysis indicated that pre-S deletion, A1762T/G1764A, A2159G, and A2189Y mutations were independently related with HCC development. Moreover, a significant biological gradient of HCC risk by number of mutations in the C gene was observed. Longitudinal observation demonstrated a gradual combination of the above mutations accumulated during the progression of HCC.

Highlights

Hepatocellular carcinoma (HCC) is a global health problem, as it is the fifth most common cancer and the third leading cause of cancer-related death [1]
In stage 1, the full sequences of hepatitis B virus (HBV) in 30 HCC cases and 30 controls were determined by PCR direct sequencing
When we examined HBV DNA sequences in the pre-S and Enh II/basal core promoter (BCP) regions, pre-S deletion, C1653T, and A1762T/G1764A, double mutations were significantly associated with HCC, showing adjusted odds ratios (ORs) from 1.929 to 2.385 (Table 3)

Summary

Introduction

Hepatocellular carcinoma (HCC) is a global health problem, as it is the fifth most common cancer and the third leading cause of cancer-related death [1]. The HBV genome comprises a partially double-stranded circular DNA molecule of approximately 3200 base pairs. This DNA strand encodes four overlapping open reading frames (ORFs): X, for the X protein; precore/core (C), for the nucleocapsid; pre-S/S, for the surface/envelope protein; and P, for the DNA polymerase [4]. The township of Qidong is one of the highest endemic regions for HBV-related HCC in China In this two-stage study, the complete HBV genome was initially analyzed in the serums of patients from a prospective cohort of male HBV carriers in Qidong, in order to explore new mutation biomarkers of HCC development in addition to traditional hot-spot mutations in pre-S and X genes. Sequential serum sequencings of the C gene were carried out to assess the longitudinal evolution of mutations in the C gene during HCC development

Results

Discussion

Conclusion