Gang Hu1, Ming X Huang1, Wei Y Li2, Chong J Gan1, Wen X Dong1, Xiao M Peng3. 1. Center of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-Sen University, 52 Meihua East Road, Zhuhai, 519000, Guangdong, China. 2. Jining Medical University, Jining, 272057, Shandong, China. 3. Center of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-Sen University, 52 Meihua East Road, Zhuhai, 519000, Guangdong, China. xiaomoupeng@hotmail.com.
Abstract
BACKGROUND: HBV integration is suspected to be an obstinate risk factor for hepatocellular carcinoma (HCC) in the era of antiviral therapy. Integration events start to occur in the immunotolerance phase, but their fates in the immune clearance phase have not yet been clarified. Here, we report the influences of liver damage on HBV integration and clonal hepatocyte expansion in patients with chronic hepatitis B (CHB). METHODS: HBV integration breakpoints in liver biopsy samples from 54 CHB patients were detected using a modified next-generation sequencing assay. RESULTS: A total of 3729 (69 per sample) integration breakpoints were found in the human genome, including some hotspot genes and KEGG pathways, especially in patients with abnormal transaminases. The number of breakpoint types, an integration risk parameter, was negatively correlated with HBV DNA load and transaminase levels. The average, maximum and total frequencies of given breakpoint types, parameters of clonal hepatocyte expansion, were negatively correlated with HBV DNA load, transaminase levels and liver inflammation activity grade score. The HBV DNA load and inflammation activity grade score were further found to be positively correlated with transaminase levels. Moreover, nucleos(t)ide analog (NUC) treatment that normalized transaminases nonsignificantly reduced the types, but significantly increased the average frequency and negated the enrichments of integration breakpoints. CONCLUSION: Liver damage mainly removed the inventories of viral integration and clonal hepatocytes in CHB. NUC treatment may have reduced HBV integration but clearly increased clonal hepatocyte expansion, which may explain why HCC risk cannot be ruled out by NUC treatment.
BACKGROUND:HBV integration is suspected to be an obstinate risk factor for hepatocellular carcinoma (HCC) in the era of antiviral therapy. Integration events start to occur in the immunotolerance phase, but their fates in the immune clearance phase have not yet been clarified. Here, we report the influences of liver damage on HBV integration and clonal hepatocyte expansion in patients with chronic hepatitis B (CHB). METHODS:HBV integration breakpoints in liver biopsy samples from 54 CHB patients were detected using a modified next-generation sequencing assay. RESULTS: A total of 3729 (69 per sample) integration breakpoints were found in the human genome, including some hotspot genes and KEGG pathways, especially in patients with abnormal transaminases. The number of breakpoint types, an integration risk parameter, was negatively correlated with HBV DNA load and transaminase levels. The average, maximum and total frequencies of given breakpoint types, parameters of clonal hepatocyte expansion, were negatively correlated with HBV DNA load, transaminase levels and liver inflammation activity grade score. The HBV DNA load and inflammation activity grade score were further found to be positively correlated with transaminase levels. Moreover, nucleos(t)ide analog (NUC) treatment that normalized transaminases nonsignificantly reduced the types, but significantly increased the average frequency and negated the enrichments of integration breakpoints. CONCLUSION:Liver damage mainly removed the inventories of viral integration and clonal hepatocytes in CHB. NUC treatment may have reduced HBV integration but clearly increased clonal hepatocyte expansion, which may explain why HCC risk cannot be ruled out by NUC treatment.
Entities:
Keywords:
Chronic hepatitis B; Clonal expansion; Hepatitis B virus; Hepatocarcinogenesis; Hepatocellular carcinoma; High-throughput viral integration detection; Immune clearance; Inflammation activity; Liver biopsy; Liver damage; Next-generation DNA sequencing; Viral DNA integration
Authors: Seung Up Kim; Yeon Seok Seo; Han Ah Lee; Mi Na Kim; Eun Ju Lee; Hye Jung Shin; Yu Rim Lee; Hye Won Lee; Jun Yong Park; Do Young Kim; Sang Hoon Ahn; Kwang-Hyub Han; Soon Ho Um; Won Young Tak; Young Oh Kweon; Beom Kyung Kim; Soo Young Park Journal: Cancer Epidemiol Biomarkers Prev Date: 2020-01-27 Impact factor: 4.254