Distribution and difference of APOBEC-induced mutations in the TpCpW context of HBV DNA between HCC and non-HCC

Hepatitis B virus (HBV) DNA is vulnerable to editing by human apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases. However, the distribution of APOBEC-induced mutations on HBV DNA is not well characterized. To this end, we obtained the HBV DNA sequence of HBV-infected individuals with and without hepatocellular carcinoma (HCC and non-HCC groups, respectively) from NCBI database and calculated the r_apo values of APOBEC-induced TpCpW→TpKpW mutation prevalence in HBV DNA. The results showed that the APOBEC-induced mutations were mainly distributed in the minus strand of non-HCC-derived HBV DNA (r_apo  = 2.04), while the mutation on the plus-strand was weaker (r_apo  = 0.99). There were high APOBEC-induced mutation regions in the minus strand of HBV DNA 1 to 1000 nucleotides (nts) region and in the plus-strand of HBV DNA 1000 to 1500 nts region; the mutations in the 1 to 1000 nts region were mainly TpCpW→TpTpW mutation types (total T/G: 111/18) and a number of these were missense mutations (missense/synonymous: 35/94 in P gene, 17/15 in S gene, and 5/10 in X gene). The difference between minus to plus-strand r_apo of HCC-derived HBV DNA (1.96) was greater than that of the non-HCC group (1.05). The minus-strand r_apo of HCC-derived HBV DNA regions 1000 to1500nts and 1500 to 2000 nts (r_apo = 4.2 and 4.2) was also higher than that of the same regions of non-HCC-derived HBV DNA (r_apo  = 1.2 and 1.1). Finally, the ratio of minus to plus-strand r_apo was used to distinguish HCC-derived HBV DNA from non-HCC-derived HBV DNA. This study unraveled the distribution characteristics of APOBEC-induced mutations on double strands of HBV DNA from HCC and non-HCC samples. Our findings would help understand the mechanism of APOBECs on HBV DNA and may provide important insights for the screening of HCC.