Abstract
Hepatitis B virus (HBV) is one of the most widespread human pathogens causing chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). This study investigated the clinical impact of single and combinational mutations in HBx gene on the pathogenesis of HCC during progressive stages of liver disease. The patients were categorized into inactive HBV carriers, active carriers, cirrhosis and HCC groups based on disease severity. Male sex, age > 50 years, and high serum alanine aminotransferase level were associated with risk of progressive liver disease. I127T, V131I, and F132Y/I/R mutations showed a significant increasing trend associated with the disease progression to HCC. H94Y and K130M mutations were also significantly associated with severe liver disease. One double mutation (K130M+V131I) and two triple mutations (I127T+K130M+V131L and K130M+V131I+F132Y) were observed, with significant rising prevalence through progressive clinical phases of liver disease to HCC. Several single and combinational mutations in HBx correlating with severity and progressive clinical phases of HBV infection were identified. The mutational combinations may have a synergistic effect in accelerating the progression to HCC. These specific patterns of HBx mutations can be useful in predicting the clinical outcome of HBV-infected patients and may serve as early markers of high risk of developing HCC.
Highlights
Hepatitis B virus (HBV) is the major causative agent of hepatitis worldwide
HBx detected in hepatocellular carcinoma (HCC) patients is known to frequently harbor mutations, which may play a role in the progression of HBV infection [12]
Mutation at position 88 of HBx protein was associated with liver cirrhosis in Indian population [15], while a Chinese study has found a mutation at amino acid 88 more frequent in HCC samples [16]
Summary
Hepatitis B virus (HBV) is the major causative agent of hepatitis worldwide. According to World Health Organization (WHO), an estimated 240 million people globally have chronic HBV infection (http:// www.who.int/mediacentre/factsheets/fs204/en/). Compared to the other three HBV proteins, a limited number of studies have examined the role of HBx mutations in the oncogenic potential of the virus. Previous studies have shown that the majority of HBx detected in HCC tissues had mutations that may alter the function of HBx [10, 11]. HBx mutants harboring both point mutations and deletions, especially C-terminal truncations, have been frequently detected in HCC patients [10, 12, 13]. Taken together, these studies suggest that HBx plays a crucial role in the pathogenesis and progression of HBV-related complications
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