Case Control Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 7, 2022; 28(33): 4812-4822
Published online Sep 7, 2022. doi: 10.3748/wjg.v28.i33.4812
Previous hepatitis B viral infection–an underestimated cause of pancreatic cancer
Sergey Batskikh, Sergey Morozov, Alexey Dorofeev, Zanna Borunova, Dmitry Kostyushev, Sergey Brezgin, Anastasiya Kostyusheva, Vladimir Chulanov
Sergey Batskikh, Department of Hepatology, Moscow Clinical Scientific Center N.A. A.S. Loginov, Moscow 111123, Russia
Sergey Morozov, Department of Gastroenterology, Hepatology and Nutrition, Federal Research Center of Nutrition, Biotechnology and Food Safety, Moscow 115446, Russia
Alexey Dorofeev, Zanna Borunova, Department of Scientific and Clinical Laboratory Research, Moscow Clinical Scientific Center N.A. A.S. Loginov, Moscow 111123, Russia
Dmitry Kostyushev, Sergey Brezgin, Anastasiya Kostyusheva, Vladimir Chulanov, Laboratory of Genetic Technologies, Sechenov University, Moscow 119435, Russia
Dmitry Kostyushev, Sergey Brezgin, Vladimir Chulanov, Division of Biotechnology, Scientific Center for Genetics and Life Sciences, Sirius University of Science and Technology, Sochi 354340, Russia
Vladimir Chulanov, Laboratory of Genetic Technologies and Translational Research, National Medical Research Center for Tuberculosis and Infectious Diseases of Ministry of Health of Russia, Moscow 127994, Russia
Author contributions: Batskikh S and Morozov S designed this study; Batskikh S collected and analyzed the data; Borunova Z, Dorofeev A, Kostyushev D, Brezgin S, Kostyusheva A and Chulanov V performed laboratory analyses; Batskikh S, Morozov S and Kostyushev D prepared the figures; Batskikh S performed statistical analysis; Morozov S and Batskikh S drafted the manuscript; All authors critically revised the manuscript and approved its final version.
Supported by Ministry of Science and Higher Education of Russian Federation, No. FGMF-2022-0005; Russian Science Foundation, No. 20-15-00373; and Moscow Healthcare Department, No. AAAA-A18-118021590196-1.
Institutional review board statement: The study was reviewed and approved by the Local Ethics Committee of Moscow Clinical Research Center, No. 9/2016, dated 12DEC2016 and was conducted in accordance with the Declaration of Helsinki (1968) and its consequent revisions.
Informed consent statement: All subjects signed a written informed consent form before the enrollment.
Conflict-of-interest statement: Dr. Batskikh reports grants from Moscow Department of Health during the conduct of the study; personal fees from ABBVIE, personal fees from MSD, personal fees from R-PHARM, outside the submitted work. Dr. Morozov reports grants from Ministry of Science and Higher Education of Russia, during the conduct of the study; personal fees from AstraZeneca, personal fees from Dr. Falk, personal fees from AlfaSigma, grants from Russian Science Foundation, personal fees from Takeda, outside the submitted work. Dr. Chulanov reports grants from Russian Foundation for Basic Research, grants from Russian Foundation for Basic Research, outside the submitted work. Dr. Kostyushev, Dr. Kostyusheva and Dr. Brezgin report grants from Russian Foundation for Basic Research, grants from Russian Foundation for Basic Research, during the conduct of the study. Dr. Dorofeev and Dr. Borunova have nothing to disclose.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Sergey Morozov, MD, PhD, Doctor, Senior Researcher, Department of Gastroenterology, Hepatology and Nutrition, Federal Research Center of Nutrition, Biotechnology and Food Safety, Kashirskoye Shosse 21, Moscow 115446, Russia. morosoffsv@mail.ru
Received: April 20, 2022
Peer-review started: April 20, 2022
First decision: June 2, 2022
Revised: June 15, 2022
Accepted: August 16, 2022
Article in press: August 16, 2022
Published online: September 7, 2022
Abstract
BACKGROUND

The etiology of pancreatic cancer remains unclear. This limits the possibility of prevention and effective treatment. Hepatitis B virus (HBV) is responsible for the development of different types of cancer, but its role in pancreatic cancer is still being discussed.

AIM

To assess the prevalence of previous HBV infection and to identify viral biomarkers in patients with pancreatic ductal adenocarcinoma (PDAC) to support the role of the virus in etiology of this cancer.

METHODS

The data of 130 hepatitis B surface antigen-negative subjects were available for the final analysis, including 60 patients with PDAC confirmed by cytology or histology and 70 sex- and age-matched controls. All the participants were tested for HBV biomarkers in blood [antibody to hepatitis B core antigen (anti-HBc), antibody to hepatitis B surface antigen (anti-HBs) and HBV DNA], and for those with PDAC, biomarkers in resected pancreatic tissues were tested (HBV DNA, HBV pregenomic RNA and covalently closed circular DNA). We performed immunohistochemistry staining of pancreatic tissues for hepatitis B virus X antigen and Ki-67 protein. Non-parametric statistics were used for the analysis.

RESULTS

Anti-HBc was detected in 18/60 (30%) patients with PDAC and in 9/70 (13%) participants in the control group (P = 0.029). Accordingly, the odds of PDAC in anti-HBc-positive subjects were higher compared to those with no previous HBV infection (odds ratio: 2.905, 95% confidence interval: 1.191-7.084, standard error 0.455). HBV DNA was detected in 8 cases of PDAC and in 6 of them in the pancreatic tumor tissue samples only (all patients were anti-HBc positive). Blood HBV DNA was negative in all subjects of the control group with positive results of the serum anti-HBc test. Among 9 patients with PDAC, 5 revealed signs of replicative competence of the virus (covalently closed circular DNA with or without pregenomic RNA) in the pancreatic tumor tissue samples. Hepatitis B virus X antigen expression and active cell proliferation was revealed by immunohistochemistry in 4 patients with PDAC in the pancreatic tumor tissue samples.

CONCLUSION

We found significantly higher risks of PDAC in anti-HBc-positive patients. Detection of viral replication and hepatitis B virus X protein expression in the tumor tissue prove involvement of HBV infection in pancreatic cancer development.

Keywords: Hepatitis B virus, Previous hepatitis B, Occult hepatitis B virus infection, Pancreatic cancer, Pancreatic ductal adenocarcinoma

Core Tip: Hepatitis B viral (HBV) infection is responsible for different types of cancer. Its role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study assessed the prevalence of previous HBV infection and to identify viral biomarkers in patients with PDAC to support the role of the virus in the etiology of this cancer. Anti-HBc-positive subjects had an almost 3-fold greater chance of PDAC compared to the controls. Detection of viral replication and hepatitis B virus X protein expression in the tumor tissue show a possible involvement of HBV infection in pancreatic cancer development. Previous HBV infection is currently an underestimated cause of PDAC.