Retrospective Cohort Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 14, 2021; 27(34): 5737-5752
Published online Sep 14, 2021. doi: 10.3748/wjg.v27.i34.5737
MTNR1B polymorphisms with CDKN2A and MGMT methylation status are associated with poor prognosis of colorectal cancer in Taiwan
Chia-Cheng Lee, Yu-Cheng Kuo, Je-Ming Hu, Pi-Kai Chang, Chien-An Sun, Tsan Yang, Chuan-Wang Li, Chao-Yang Chen, Fu-Huang Lin, Chih-Hsiung Hsu, Yu-Ching Chou
Chia-Cheng Lee, Je-Ming Hu, Pi-Kai Chang, Chao-Yang Chen, Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
Chia-Cheng Lee, Medical Informatics Office, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
Yu-Cheng Kuo, Fu-Huang Lin, Chih-Hsiung Hsu, Yu-Ching Chou, School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
Chien-An Sun, Department of Public Health, College of Medicine, Fu-Jen Catholic University, New Taipei City 24205, Taiwan
Chien-An Sun, Big Data Research Center, College of Medicine, Fu-Jen Catholic University, New Taipei City 24205, Taiwan
Tsan Yang, Department of Health Business Administration, Meiho University, Pingtung 91202, Taiwan
Chuan-Wang Li, Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei 114, Taiwan
Chuan-Wang Li, Institute of Preventive Medicine, National Defense Medical Center, New Taipei City 237, Taiwan
Author contributions: Hsu CH and Chou YC contributed equally to this work; Lee CC, Hsu CH and Chou YC designed the research; Sun CA, Yang T and Li CW performed the research; Hu JM, Chang PK and Chen CY collected the data; Lee CC, Kuo YC, Hsu CH, Lin FH and Chou YC analyzed the data; Lee CC, Hsu CH and Chou YC wrote the paper.
Supported by the grant from the Ministry of National Defense-Medical Affairs Bureau, Taiwan, No. MND-MAB-110-109 and No. MND-MAB-D-111059.
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.
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: Yu-Ching Chou, PhD, Professor, School of Public Health, National Defense Medical Center, No. 161 Sec. 6, Minquan E. Road, Neihu District, Taipei 114, Taiwan.
Received: April 15, 2021
Peer-review started: April 15, 2021
First decision: June 23, 2021
Revised: June 30, 2021
Accepted: August 23, 2021
Article in press: August 23, 2021
Published online: September 14, 2021
Research background

Melatonin plays a central role in the management of circadian rhythm and was identified in the gastrointestinal tract. Epidemiological studies demonstrated that melatonin has oncostatic effects including induction of epigenetic alteration on different types of tumours. The melatonin receptor MT2 encoded by MTNR1B is generally responsible for mediating the downstream effects of melatonin. The expression of MT2 in tumour mucosa is lower than the normal mucosa in patients with colorectal cancer (CRC).

Research motivation

Growing studies have investigated the association between melatonin and CRC carcinogenesis. However, the relationship between MTNR1B gene polymorphisms and CRC sensitivity is not clear. To analyze the effects of MTNR1B gene polymorphisms on CRC prognosis and evaluate the interactions with aberrant promoter methylation of the CDKN2A and MGMT genes will be of great significance.

Research objectives

In our study, we aimed to explore the association between MTNR1B single-nucleotide polymorphism (SNPs) and the 5-year overall survival (OS) of CRC patients. To further assess the interaction between MTNR1B SNPs and CDKN2A and MGMT gene methylation, we examined the relationship between each SNP and the 5-year OS, with data stratified by the methylation status of the CDKN2A and MGMT gene.

Research methods

Ninety four CRC patients from Taiwan were enrolled to evaluate the association between MTNR1B SNPs, CDKN2A, MGMT gene hypermethylation and 5-year OS. The MTNR1B gene polymorphisms were screened using the Agena MassARRAY platform with iPLEX gold chemistry. The promoter methylation status of CDKN2A and MGMT was assessed using methylation-specific polymerase chain reaction. Associations of the genetic and epigenetic effect and 5-year OS were assessed using the Cox proportional hazards regression model.

Research results

In this retrospective cohort study, we found that MTNR1B SNPs was associated with a significantly increased risk of CRC 5-year OS. A strong cumulative effect of the four polymorphisms on CRC prognosis was observed. In stratified analysis, rs1387153, and rs1447352 risk genotype were determined to be associated with 5-year OS in the unmethylation MGMT gene subgroup. In contrast, rs10830963 and rs1447352 risk genotype with hypermethylation CDKN2A gene had a higher risk of death in five years. Four haplotypes of MTNR1B SNPs were also determined to be associated with increased risk of mortality.

Research conclusions

This study is one of few reports which demonstrated the association between MTNR1B SNPs and the 5-year OS in patients with CRC. Our data identified these novel genetic biomarkers combined with CDKN2A and MGMT methylation status for the prediction of CRC prognosis, and the findings could be used to individualise the treatment of patients with CRC.

Research perspectives

Based on our findings, the novel genetic biomarkers, MTNR1B, combined with CDKN2A and MGMT gene methylation statuses could be a predictive tool for CRC prognosis. The new set of markers may help physicians make treatment decisions based on the prognostic information and would improve the OS of patients with CRC. This study warrant further investigation of the underlying mechanisms related to oncostatic effects of MTNR1B on CRC.