Retrospective Cohort Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 14, 2020; 26(2): 154-167
Published online Jan 14, 2020. doi: 10.3748/wjg.v26.i2.154
Novel methylation gene panel in adjacent normal tissues predicts poor prognosis of colorectal cancer in Taiwan
Chih-Hsiung Hsu, Cheng-Wen Hsiao, Chien-An Sun, Wen-Chih Wu, Tsan Yang, Je-Ming Hu, Chi-Hua Huang, Yu-Chan Liao, Chao-Yang Chen, Fu-Huang Lin, Yu-Ching Chou
Chih-Hsiung Hsu, Je-Ming Hu, Yu-Ching Chou, Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan
Chih-Hsiung Hsu, Teaching Office, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
Cheng-Wen Hsiao, Je-Ming Hu, Chao-Yang Chen, Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
Chien-An Sun, Department of Public Health, College of Medicine, Fu-Jen Catholic University, New Taipei City 242, Taiwan
Chien-An Sun, Big Data Research Center, College of Medicine, Fu-Jen Catholic University, New Taipei City 242, Taiwan
Wen-Chih Wu, Chi-Hua Huang, Yu-Chan Liao, Fu-Huang Lin, Yu-Ching Chou, School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
Wen-Chih Wu, Department of Surgery, Suao and Yuanshan Branches of Taipei Veterans General Hospital, Yilan County 264, Taiwan
Tsan Yang, Department of Health Business Administration, Meiho University, Pingtung County 912, Taiwan
Je-Ming Hu, Chao-Yang Chen, Adjunct Instructor, School of Medicine, National Defense Medical Center, Taipei 114, Taiwan
Author contributions: Hsu CH and Chou YC designed the research; Hsiao CW, Sun CA, Wu WC, and Yang T performed the research; Hsiao CW, Hu JM, and Chen CY collected the data; Hsu CH, Huang CH, Liao YC, Lin FH, and Chou YC analyzed the data; Hsu CH and Chou YC wrote the paper.
Supported by the Ministry of Science and Technology, Taiwan, No. MOST 104-2314-B-016-010-MY2 and No. MOST 106-2320-B-016-018; and the Ministry of National Defense, Taiwan, No. MAB-107-075, No. MAB-108-057 and No. MAB-109-061.
Institutional review board statement: This study was approved by the TSGH Institutional Review Board (TSGHIRB approval number: 098-05-292 and 2-105-05-129).
Informed consent statement: Written informed consent was obtained from all patients before enrollment into the study to evaluate their prognosis.
Conflict-of-interest statement: We have no financial relationships 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 which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Yu-Ching Chou, PhD, Associate Professor, School of Public Health, National Defense Medical Center, No. 161 Sec. 6, Minquan E. Road, Neihu District, Taipei 114, Taiwan. trishow@mail.ndmctsgh.edu.tw
Received: October 24, 2019
Peer-review started: October 24, 2019
First decision: December 5, 2019
Revised: December 14, 2019
Accepted: December 21, 2019
Article in press: December 21, 2019
Published online: January 14, 2020
Abstract
BACKGROUND

It is evident that current clinical criteria are suboptimal to accurately estimate patient prognosis. Studies have identified epigenetic aberrant changes as novel prognostic factors for colorectal cancer (CRC).

AIM

To estimate whether a methylation gene panel in different clinical stages can reflect a different prognosis.

METHODS

We enrolled 120 CRC patients from Tri-Service General Hospital in Taiwan and used the candidate gene approach to select six genes involved in carcinogenesis pathways. Patients were divided into two groups based on the methylation status of the six evaluated genes, namely, the < 3 aberrancy group and ≥ 3 aberrancy group. Various tumor stages were divided into two subgroups (local and advanced stages) on the basis of the pathological type of the following tissues: Tumor and adjacent normal tissues (matched normal). We assessed DNA methylation in tumors and adjacent normal tissues from CRC patients and analyzed the association between DNA methylation with different cancer stages and the prognostic outcome including time to progression (TTP) and overall survival.

RESULTS

We observed a significantly increasing trend of hazard ratio as the number of hypermethylated genes increased both in normal tissue and tumor tissue. The 5-year TTP survival curves showed a significant difference between the ≥ 3 aberrancy group and the < 3 aberrancy group. Compared with the < 3 aberrancy group, a significantly shorter TTP was observed in the ≥ 3 aberrancy group. We further analyzed the interaction between CRC prognosis and different cancer stages (local and advanced) according to the methylation status of the selected genes in both types of tissues. There was a significantly shorter 5-year TTP for tumors at advanced stages with the promoter methylation status of selected genes than for those with local stages. We found an interaction between cancer stages and the promoter methylation status of selected genes in both types of tissues.

CONCLUSION

Our data provide a significant association between the methylation markers in normal tissues with advanced stage and prognosis of CRC. We recommend using these novel markers to assist in clinical decision-making.

Keywords: DNA methylation, Panel genes, Clinical stage, Prognosis outcome, Adjacent normal tissues, Colorectal cancer

Core tip: Our data show that a novel methylation gene panel in adjacent normal tissues predicts a poor prognosis of colorectal cancer. We recommend that the matched normal tissues of patients with colorectal cancer could be an alternative source of prognostic markers to assist clinical decision-making.