Clinical utility of complex mutations in the core promoter and proximal precore regions of the hepatitis B virus genome

Abstract

The core promoter and proximal precore regions are the most complex portions of the hepatitis B virus (HBV) genome. These regions cooperatively regulate viral replication and differentially regulate the synthesis of the viral proteins E, core, and X. Multiple mutations in these regions are associated with the persistency of viral infection and the development of cirrhosis and hepatocellular carcinoma (HCC). In South Korea, nearly all HBVs are classified as HBV genotype C2; the majority of these viruses have the basal core promoter double mutation, a precore stop mutation, or both. These mutations may play a role in the alteration of viral and clinical features, and abundant and complex mutations are particularly prevalent in the core promoter and proximal precore regions. We previously demonstrated that the accumulation of ≥ 6 mutations at eight key nucleotides located in these regions (G1613A, C1653T, T1753V, A1762T, G1764A, A1846T, G1896A, and G1899A) is a useful marker to predict the development of HCC regardless of advanced liver disease. In addition, certain mutation combinations were predominant in cases with ≥ 4 mutations. In cases with ≤ 5 mutations, a low Hepatitis B e antigen titer (< 35 signal to noise ratio) was indicative of HCC risk. Viral mutation data of the single HBV genotype C2 suggest that the combined effect of the number and pattern of mutations in the core promoter and proximal precore regions is helpful in predicting HCC risk.

Clinical features of HBsAg seroclearance in hepatitis B virus carriers in South Korea: A retrospective longitudinal study

“…In Korea, where most HBV carriers harbor genotype C2[8-10], most carriers over the age of 40 are infected with HBV with basal core promoter (BCP) double mutations (A1762G and A1764T), and more than half of these individuals have the G1896A mutation[9,10]. These mutations are associated with HBeAg-negative chronic hepatitis that is frequently reactivated[2,11,12], and HBeAg seroconversion is associated with the development of LC and HCC in two-thirds of carriers[2,7,13]. Because the turning point of seroconversion generally occurs near the age of 40[11], the recovery phase and timing of mutations usually overlap with the development of LC and HCC at this time[2,14].…”

“…These mutations are associated with HBeAg-negative chronic hepatitis that is frequently reactivated[2,11,12], and HBeAg seroconversion is associated with the development of LC and HCC in two-thirds of carriers[2,7,13]. Because the turning point of seroconversion generally occurs near the age of 40[11], the recovery phase and timing of mutations usually overlap with the development of LC and HCC at this time[2,14]. However, HCC may also develop after HBsAg seroclearance[2,14].…”

Comparison Study on Characteristics of Hepatitis B Virus Whole Genomes for Hepatocellular Carcinoma and Chronic Hepatitis B Patients

“…Various types of mutations to the HBV genome have been reported, resulting amino acid substitutions during long-term infection, some of which could serve as markers to predict the development of HBV-associated HCC [4] , such as mutations in the pre-surface antigen (pre-S) (i.e., deletion to the preS1 [W4P/R] and pre-S2 start codon deletion, pre-core (i.e., nucleotide 1896(G1896A), or a double mutation to the basal core promoter (BCP) and X regions (V5M) [5] .…”

Comparison of the Characteristics of Hepatitis B Virus Whole Genomes Derived From Patients With Hepatocellular Carcinoma and Chronic Hepatitis B Infection

“…Various types of mutations to the HBV genome have been reported, resulting amino acid substitutions during long-term infection, some of which could serve as markers to predict the development of HBV-associated HCC [6,7], such as mutations in the pre-surface antigen (pre-S) (i.e., deletion to the preS1 [W4P/R] and pre-S2 start codon deletion, pre-core (i.e., nucleotide 1896(G1896A), or a double mutation to the basal core promoter (BCP) and X regions (V5M) [8][9][10].…”