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©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Pathophysiol. Mar 22, 2023; 14(2): 21-33
Published online Mar 22, 2023. doi: 10.4291/wjgp.v14.i2.21
Polymorphism of genes encoding drug-metabolizing and inflammation-related enzymes for susceptibility to cholangiocarcinoma in Thailand
Gyokukou You, Lu Zeng, Hideaki Tanaka, Emi Ohta, Takahiro Fujii, Kazuhiko Ohshima, Masakazu Tanaka, Nobuyuki Hamajima, Chutiwan Viwatthanasittiphong, Mantana Muangphot, Dhiraphol Chenvidhya, Adisorn Jedpiyawongse, Banchob Sripa, Masanao Miwa, Satoshi Honjo
Gyokukou You, Lu Zeng, Hideaki Tanaka, Emi Ohta, Takahiro Fujii, Kazuhiko Ohshima, Masanao Miwa, Department of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Shiga, Japan
Masakazu Tanaka, Division of Neuroimmunology, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima 890-8544, Kagoshima, Japan
Nobuyuki Hamajima, Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Aichi, Japan
Chutiwan Viwatthanasittiphong, Department of Diagnostic and Interventional Radiology, Ubon Cancer Centre, Ubon Ratchathani 34000, Thailand
Mantana Muangphot, Department of Pathology, Ubon Cancer Centre, Ubon Ratchathani 34000, Thailand
Dhiraphol Chenvidhya, Department of Surgery, Ubon Cancer Centre, Ubon Ratchathani 34000, Thailand
Adisorn Jedpiyawongse, Research Division, National Cancer Institute, Bangkok 10400, Thailand
Banchob Sripa, Department of Pathology, Khon Kaen University, Khon Kaen 40002, Thailand
Satoshi Honjo, Department of Paediatirics, National Hospital Organization, Fukuoka National Hospital, Fukuoka 811-1394, Fukuoka, Japan
Author contributions: Miwa M secured funds and started the collaborative study in 1998 with the late Srivatanakul P who had been Thai side’s active organizer based on the National Cancer Institute, Bangkok, until her death in 2020; Viwatthanasittiphong C, Muangphot M, Chenvidhya D, Jedpiyawongse A, Sripa B, Honjo S, and Miwa M designed and conducted the epidemiological study; Sripa B measured anti-OV and providing microbiological advice; You G, Zeng L, Tanaka H, Ohta E, Fujii T, Ohshima K, Tanaka M, Hamajima N performed analyses concerning genetic polymorphisms; You G, Zeng L, Miwa M and Honjo S conducted statistical analyses and prepared the manuscript; All authors have read and approved the final manuscript.
Supported by Japan Society for the Promotion of Science, No. 21406011.
Institutional review board statement: This work was conducted after receiving the approval from the ethics committees of the Nagahama Institute of Bio-Science and Technology, Shiga, Japan, and the National Cancer Institute, Bangkok, Thailand.
Informed consent statement: Informed written consent was obtained from the case and control subjects for publication of this report and any accompanying images.
Conflict-of-interest statement: All authors declare that they have no competing interests.
Data sharing statement: Consent for data sharing was not obtained.
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: Satoshi Honjo, MD, MSc, PhD, Chief Doctor, Senior Researcher, Department of Paediatirics, National Hospital Organization, Fukuoka National Hospital, 1-39-4 Yakatabaru, Minami-ku, Fukuoka 811-1394, Fukuoka, Japan. satoshihonjo@hotmail.com
Received: December 11, 2022
Peer-review started: December 11, 2022
First decision: February 8, 2023
Revised: February 19, 2023
Accepted: March 15, 2023
Article in press: March 15, 2023
Published online: March 22, 2023
Processing time: 99 Days and 14 Hours
ARTICLE HIGHLIGHTS
Research background
Cholangiocarcinoma (CCA) is a cancer of the hepatobiliary tract, and its incidence is extremely high in northeastern Thailand. This is related to the lifestyle of the inhabitants of this area consuming often raw fish, which carries the risk of ingesting fish-borne parasites, Opisthorchis viverrini (OV), a known CCA risk factor. While infection with OV has been listed as a carcinogen to humans by The International Agency for Research on Cancer, the parasitic infection alone is not sufficient to develop CCA; in fact, co-administration of a chemical carcinogen such as N-nitrosodimethylamine is necessary to induce CCA in animal model. In addition, genetic background related to the activation or detoxification of chemical carcinogens is reported to be involved in CCA risk. Also, elevated plasma IL-6 was associated with increased risk of CCA in patients infected with OV.
Research motivation
We already reported that infection with OV and genetic polymorphism of a drug-metabolizing enzyme gene, namely GSTM1, is related to CCA risk and that the combined effect of polymorphisms of the genes 8-oxoguanine glycosylase 1 and GSTM1 is also relevant CCA risk in northeastern Thailand. In the present study, we further investigated possible associations of maintenance of chronic infection, exposure to a chemical carcinogen(s) and genetic background with CCA risk in northeastern Thailand.
Research objectives
To examine relations between risk for CCA and genetic polymorphisms in carcinogen-metabolizing (CYP2E1, GSTT1 and GSTM1) and inflammation-related genes (IL-6, IL-10 and NF-kB), and potential interactions among genetic polymorphisms of these genes on the CCA risk.
Research methods
All cases with CCA were identified between 1999 and 2005 upon a visit to the Ubon Ratchathani Cancer Centre in the northeastern province of Thailand. This hospital-based case-control study enrolled 95 case-control pairs matched by age (± 5 years) and sex. We examined relations between risk for CCA and genetic polymorphisms in carcinogen-metabolizing and inflammation-related genes, serum anti-OV, alcohol consumption, and smoking. Smoking and alcohol consumption status were ascertained using a structured questionnaire used in previous studies. Conditional logistic regression was employed to estimate CCA risk as OR due to each of genetic polymorphisms and possible interactions of those polymorphisms.
Research results
Although any single polymorphism was not significantly associated with CCA risk, persons with the GSTT1 wild-type and CYP2E1 c1/c2 + c2/c2 genotype had a 3-fold increased risk as compared with persons having the GSTT1 wild-type and CYP2E1 c1/c1 wild genotype. The presence of anti-OV in serum was associated with a 7- to 11-fold increased risk for CCA independently of the genetic polymorphisms of carcinogen-metabolizing and inflammation-related genes.
Research conclusions
An inflammatory condition produced by infection with OV indicated as raised anti-OV in serum has been associated with CCA risk. Our study added the finding that persons with the GSTT1 wild-type and CYP2E1 c1/c2 + c2/c2 genotype had a 3-fold increased risk for developing CCA. Therefore, both gene-gene interactions and OV infection should be considered as risk factors for cholangiocarcinogenesis in northeastern Thailand.
Research perspectives
CCA is still an intractable cancer. While our study revealed the interaction of polymorphisms of GSTT1 and CYP2E1 possibly contributes to development of CCA, the numbers of cases and controls were not large. The conclusions from this work should be confirmed in a future study with more cases and controls. In addition, genes encoding other drug-metabolizing enzymes should also be tested with respect to gene-gene interactions.
