Free episomal and integrated HBV DNA in HBsAg-negative patients with intrahepatic cholangiocarcinoma
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Teresa Pollicino1,2, Cristina Musolino3, Carlo Saitta1, Gianluca Tripodi3, Marika Lanza3, Giuseppina Raffa1,3, Francesca Casuscelli di Tocco3, Chiara Raggi4,7, Maria Consiglia Bragazzi5, Adalberto Barbera2,6, Giuseppe Navarra2,6, Pietro Invernizzi4,8, Domenico Alvaro5 and Giovanni Raimondo1,3
1 Division of Clinical and Molecular Hepatology, University Hospital of Messina, Italy
2 Department of Human Pathology, University of Messina, Italy
3 Department of Clinical and Experimental Medicine, University of Messina, Italy
4 Humanitas Research and Clinical Center, Rozzano, Milan, Italy
5 Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
6 Division of Surgical Oncology, University Hospital of Messina, Italy
7 Present address: Department of Experimental and Clinical Medicine, University of Florence, Italy
8 Present address: Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano – Bicocca, Milan, Italy
Keywords: hepatitis B virus; covalently closed circular HBV DNA; HBV DNA integration; intrahepatic cholangiocarcinoma; occult HBV Infection
Received: March 25, 2019 Accepted: May 20, 2019 Published: June 11, 2019
There is evidence that chronic hepatitis B virus (HBV) infection is associated with an increased risk of intrahepatic cholangiocarcinoma (ICC) development, and it has been hypothesized an etiological role of HBV in the development of this tumor. Very little is known about occult HBV infection (OBI) in ICC. Aims of the study were to investigate the OBI prevalence and to characterize the HBV molecular status at intrahepatic level in OBI-positive cases with ICC.
Frozen liver tumor specimens from 47 HBV surface-antigen-negative patients with ICC and 41 paired non-tumor liver tissues were tested for OBI by 4 different HBV-specific nested PCR. Covalently closed circular HBV DNA (HBV cccDNA) and viral integrations were investigated in OBI-positive cases.
HBV DNA was detected in tumor and/or non-tumor specimens from 29/47 (61.7%) ICC patients. HBV cccDNA was found in tissues from 5/17 (34.5%) cases examined. HBV integration was detected in 4/10 (40%) tumor tissues tested and involved HBx and HBV-core gene sequences in 3 and 1 cases, respectively. Viral integration occurred: (a) 9,367 nucleotides upstream of the cat-eye-syndrome critical region protein-5-isoform coding sequence; (b) within the cystinosin isoform-1-precursor gene; (c) within the thromboxane-A-synthase-1 gene; (d) within the ATPase phospholipid transporting 9B gene.
Occult HBV infection is highly prevalent in patients with ICC. Both free viral genomes and integrated HBV DNA can be present in these cases. These results suggest an involvement of HBV in the carcinogenic process leading to ICC development even in cases with occult infection.
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