Genetic Polymorphisms Predisposing the Interleukin 6–Induced APOBEC3B-UNG Imbalance Increase HCC Risk via Promoting the Generation of APOBEC-Signature HBV Mutations

Abstract

Purpose: APOBEC3-UNG imbalance contributes to hepatitis B virus (HBV) inhibition and somatic mutations. We aimed to explore the associations between hepatocellular carcinoma (HCC) risk and genetic polymorphisms predisposing the imbalance. Experimental Design: Genetic polymorphisms at APOBEC3 promoter and UNG enhancer regions were genotyped in 5,621 participants using quantitative PCR. HBV mutations (nt.1600-nt.1945, nt.2848-nt.155) were determined by Sanger sequencing. Dual-luciferase reporter assay was applied to detect the transcriptional activity. Effects of APOBEC3B/UNG SNPs and expression levels on HCC prognosis were evaluated with a cohort of 400 patients with HCC and public databases, respectively. Results: APOBEC3B rs2267401-G allele and UNG rs3890995-C allele significantly increased HCC risk. rs2267401-G allele was significantly associated with the generation of APOBEC-signature HBV mutation whose frequency consecutively increased from asymptomatic HBV carriers to patients with HCC. Multiplicative interaction of rs2267401-G allele with rs3890995-C allele increased HCC risk, with an adjusted OR (95% confidence interval) of 1.90 (1.34-2.81). rs2267401 T-to-G and rs3890995 T-to-C conferred increased activities of APOBEC3B promoter and UNG enhancer, respectively. IL6 significantly increased APOBEC3B promoter activity and inhibited UNG enhancer activity, and these effects were more evident in those carrying rs2267401-G and rs3890995-C, respectively. APOBEC3B rs2267401-GG genotype, higher APOBEC3B expression, and higher APOBEC3B/UNG expression ratio in HCCs indicated poor prognosis. APOBEC-signature somatic mutation predicts poor prognosis in HBV-free HCCs rather than in HBV-positive ones. Conclusions: Polymorphic genotypes predisposing the APOBEC3B-UNG imbalance in IL6-presenting microenvironment promote HCC development, possibly via promoting the generation of high-risk HBV mutations. This can be transformed into specific prophylaxis of HBV-caused HCC.

The genetic polymorphism down‐regulating HLA‐DRB1 enhancer activity facilitates HBV persistence, evolution and hepatocarcinogenesis in the Chinese Han population

“…HBV reverse transcriptase lacks proofreading activity, resulting in a mutation rate of 2.2 × 10 ‐5 substitutions/site/month 11 . Inflammatory factor‐activated nucleic acid editing enzymes such as cytidine deaminases also increase the instability of the HBV genome 12,13 . The HCC‐risk HBV mutants are then selected by immune function.…”

Histone Deacetylase Inhibitors Romidepsin and Vorinostat Promote Hepatitis B Virus Replication by Inducing Cell Cycle Arrest

“… 41 As such, the enhanced host genome mutation may also, subsequently, help the virus to escape the immune system and evolve. 42 The exact mechanism needs further investigation.…”

Hepatitis B Virus (HBV) - Induced Hepatocarcinogenesis, a Founding Framework of Cancer Evolution and Development (Cancer Evo-Dev)

“…IL-6 can increase the expression of APOBEC3B and decrease the expression of UNG. The functional polymorphisms located in the APOBEC3B promoter (rs2267401-G) and UNG enhancer (rs3890995-C) predispose the IL-6 induced APOBEC3B-UNG imbalance and increase the risk of HCC [35].…”

“…The expression levels of APOBEC3s are positively correlated with the quasispecies complexity of HBV [48]. The genetic polymorphisms predisposing the IL-6 induced APOBEC3B-UNG imbalance significantly promote the generation of HCC related HBV mutations [35]. Although many HBV genome fragments, including the Enhancer II (EnhII) / basal core promoter (BCP)/ precore region and the S region, are generally sensitive to editing by members of APOBEC3 [49][50][51][52][53], the sequence encoding HBV X protein (HBx) is more vulnerable.…”