Abstract
<div>AbstractPurpose:<p>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.</p><p><b>Experimental Design:</b> Genetic polymorphisms at <i>APOBEC3</i> promoter and <i>UNG</i> 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 <i>APOBEC3B</i>/<i>UNG</i> SNPs and expression levels on HCC prognosis were evaluated with a cohort of 400 patients with HCC and public databases, respectively.</p>Results:<p><i>APOBEC3B</i> rs2267401-G allele and <i>UNG</i> 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 <i>APOBEC3B</i> promoter and <i>UNG</i> enhancer, respectively. IL6 significantly increased <i>APOBEC3B</i> promoter activity and inhibited <i>UNG</i> enhancer activity, and these effects were more evident in those carrying rs2267401-G and rs3890995-C, respectively. <i>APOBEC3B</i> 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.</p>Conclusions:<p>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.</p></div>
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