Oncogenic HBV variants and integration are present in hepatic and lymphoid cells derived from chronic HBV patients. (28th June 2020)

• Record Type: Journal Article
• Authors: Lau, Keith CK.; Joshi, Shivali S.; Gao, Shan; Giles, Elizabeth; Swidinsky, Ken; van Marle, Guido; Bathe, Oliver F.; Urbanski, Stefan J.; Terrault, Norah A.; Burak, Kelly W.; Osiowy, Carla; Coffin, Carla S.
• Is Part Of: Cancer letters. Volume 480(2020)
• Page Start: 39
• Page End: 47
• Publication Date: 2020-06-28
• Subjects: Viral reservoirs -- Hepatocellular carcinoma -- Single nucleotide polymorphisms -- Viral integration -- Extrahepatic malignancy -- Oncogenesis; BCP basal core promotor -- cccDNA covalently closed circular DNA -- CHB Chronic hepatitis B -- DCS Dendritic cell sarcoma -- HBV Hepatitis B virus -- HBcAg Hepatitis B core antigen -- HBeAg Hepatitis e antigen -- HBsAg Hepatitis B surface antigen -- HCC Hepatocellular carcinoma -- NA Nucleot/side analogs -- NAH Nucleic acid hybridization -- NHL Non-hodgkin's lymphoma -- PBMC Peripheral blood mononuclear cells -- PC Pre-core -- PHA Phytohemagglutinin -- PWM Pokeweed mitogen -- S Surface -- SNP Single nucleotide polymorphism; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2020.03.022
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: The hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC), partly driven by viral integration and specific oncogenic HBV variants. However, the biological significance of HBV genomes within lymphoid cells (i.e., peripheral blood mononuclear cells, PBMCs) is unclear. Here, we collected available plasma, PBMC, liver, and tumor from 52 chronic HBV (CHB) carriers: 32 with HCC, 19 without HCC, and one with dendritic cell sarcoma, DCS. Using highly sensitive sequencing techniques, next generation sequencing, and AluPCR, we demonstrate that viral genomes (i.e., HBV DNA, RNA, and cccDNA), oncogenic variants, and HBV-host integration are often found in all sample types collected from 52 patients (including lymphoid cells and a DCS tumor). Viral integration was recurrently identified (n = 90 such hits) in genes associated with oncogenic consequences in lymphoid and liver cells. Further, HBV genomes increased in PBMCs derived from 7 additional (treated or untreated) CHB carriers after extracellular mitogen stimulation. Our study shows novel HBV molecular data and replication not only liver, but also within 63.8% of lymphoid cells analysed (including a representative lymphoid cell malignancy), that was enhanced in ex vivo stimulated PBMC. Highlights: HBV oncogenic variants, and integration were found in plasma, PBMCs, and liver. Viral integration was frequently identified within tumor suppressors and oncogenes. HBV infection and integration were detected in lymphoproliferative cell tumor. Stimulation of PBMCs with mitogen increased detection of viral genomes.