Retrospective Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 21, 2020; 26(39): 6047-6056
Published online Oct 21, 2020. doi: 10.3748/wjg.v26.i39.6047
Relationships of early esophageal cancer with human papillomavirus and alcohol metabolism
Masaki Inoue, Yuichi Shimizu, Marin Ishikawa, Satoshi Abiko, Yoshihiko Shimoda, Ikko Tanaka, Sayoko Kinowaki, Masayoshi Ono, Keiko Yamamoto, Shoko Ono, Naoya Sakamoto
Masaki Inoue, Yoshihiko Shimoda, Ikko Tanaka, Sayoko Kinowaki, Naoya Sakamoto, Department of Gastroenterology and Hepatology, Graduate School of Medicine and Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido 060-0808, Japan
Yuichi Shimizu, Masayoshi Ono, Keiko Yamamoto, Division of Endoscopy, Hokkaido University Hospital, Sapporo, Hokkaido 060-8648, Japan
Marin Ishikawa, Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-0808, Japan
Marin Ishikawa, Shoko Ono, Department of Gastroenterology, Hokkaido University Hospital, Sapporo, Hokkaido 060-8648, Japan
Satoshi Abiko, Department of Gastroenterology and Hepatology, Hakodate Municipal Hospital, Hakodate, Hokkaido 041-8680, Japan
Author contributions: Inoue M and Shimizu Y contributed equally to this work; Shimizu Y designed the research study; Inoue M, Shimoda Y, Tanaka I, Kinowaki S performed the research; Shimizu Y, Ono M, Yamamoto K, Ono S and Sakamoto N supervised the research; Inoue M, Shimizu Y and Abiko S analyzed data; Ishikawa M pathologically supervised the reseach; Inoue M and Shimizu Y wrote the manuscript; All authors have read and approve the final manuscript.
Institutional review board statement: This study was reviewed and approved by Hokkaido University Hospital Division of Clinical Research Administration.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymous clinical data that were obtained after each patient agreed to treatment by written consent. For full disclosure, the details of the study are published on the home page of Hokkaido University.
Conflict-of-interest statement: We have no financial relationships to disclose.
Data sharing statement: No additional data are available.
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:
Corresponding author: Yuichi Shimizu, MD, PhD, Associate Professor, Division of Endoscopy, Hokkaido University Hospital, kita 14 jo, nishi 5 chome, kita-ku, Sapporo, Hokkaido 060-8648, Japan.
Received: July 1, 2020
Peer-review started: July 1, 2020
First decision: July 28, 2020
Revised: August 13, 2020
Accepted: September 25, 2020
Article in press: September 25, 2020
Published online: October 21, 2020

It is well known that an alcohol consumption habit together with inactive heterozygous aldehyde dehydrogenase-2 (ALDH2) is an important risk factor for the development of esophageal squamous cell carcinoma (ESCC). It remains controversial whether human papillomavirus (HPV) infection contributes to the occurrence/development of ESCC. There has been no study in which the relationship between ESCC and HPV in addition to alcohol dehydrogenase-1B (ADH1B) and ALDH2 genotypes was evaluated.


To evaluate relationships between HPV infection and development of esophageal cancer, particularly early esophageal cancer, based on ADH1B/ALDH2 polymorphisms.


We conducted an exploratory retrospective study using new specimens, and we enrolled 145 patients who underwent endoscopic resection for superficial ESCC and had been observed for more than two years by both physical examination and endoscopic examination in Hokkaido University Hospital. Saliva was collected to analyze genetic polymorphisms of ADH1B/ALDH2. We performed in situ hybridization for resected specimens to detect HPV by using an HPV type 16/18 probe.


HPV was detected in 15 (10.3%) of the 145 patients with ESCC. HPV-positive rates in inactive ALDH2*1/*2 and ALDH2*1/*1 + *2/*2 were 10.8% and 9.8%, respectively (P = 1.00). HPV-positive rates in slow-metabolizing ADH1B*1/*1 and ADH1B*1/*2 + *2/*2 were 12.0% and 10.0%, respectively (P = 0.72). HPV-positive rates in the heavy or moderate alcohol consumption group and the light or rare consumption group were 11.1% and 8.7%, respectively (P = 0.68). HPV-positive rates in the heavy smoking group and the light or no smoking group were 11.8% and 8.3%, respectively (P = 0.59). The 3-year incidence rates of secondary ESCC or head and neck cancer after initial treatment in the HPV-positive and HPV-negative groups were 14.4% and 21.4% (P = 0.22), respectively.


In the present situation, HPV status is considered to be less important than other risk factors, such as alcohol consumption, smoking habit, ADH1B/ALDH2 polymorphisms, and HPV status would therefore have no effect on ESCC risk management.

Keywords: Human papillomavirus, Esophageal squamous cell carcinoma, Early esophageal cancer, Alcohol dehydrogenase-1B, Aldehyde dehydrogenase-2, Endoscopic resection

Core Tip: We examined esophageal squamous cell carcinoma (ESCC) tissues obtained by endoscopic mucosal resection or endoscopic submucosal dissection for human papillomavirus (HPV) infection. Genotyping of alcohol dehydrogenase-1B (ADH1B)/ aldehyde dehydrogenase-2 (ALDH2) by using saliva sampling was performed. As a result, significant differences were not found between HPV infection and ADH1B/ALDH2. However, results of investigations including investigation of genetic polymorphisms in alcohol metabolism were shown for the first time, and there has so far been study on only early ESCC. We therefore consider the results of our study to be important.