Systematic Reviews
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 21, 2023; 29(7): 1219-1234
Published online Feb 21, 2023. doi: 10.3748/wjg.v29.i7.1219
Influence of methyl donor nutrients as epigenetic regulators in colorectal cancer: A systematic review of observational studies
Lourdes Pilar Chávez-Hidalgo, Silvia Martín-Fernández-de-Labastida, Marian M de Pancorbo, Marta Arroyo-Izaga
Lourdes Pilar Chávez-Hidalgo, Silvia Martín-Fernández-de-Labastida, Marta Arroyo-Izaga, Department of Pharmacy and Food Sciences, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz 01006, Araba/Álava, Spain
Marian M de Pancorbo, Department of Z. and Cellular Biology A., University of the Basque Country UPV/EHU, Vitoria-Gasteiz 01006, Araba/Álava, Spain
Marian M de Pancorbo, Marta Arroyo-Izaga, BIOMICs Research Group, MICROFLUIDICs and BIOMICs Cluster UPV/EHU, Lascaray Research Center, University of the Basque Country UPV/EHU, Vitoria-Gasteiz 01006, Araba/Álava, Spain
Author contributions: The study was conceived and designed by Chávez-Hidalgo LP, Martín-Fernández-de-Labastida S, M de Pancorbo M, and Arroyo-Izaga M; The data were acquired, collated, and analysed by Chávez-Hidalgo LP and Arroyo-Izaga M; The study was drafted and revised critically for important intellectual content by all authors; The work reported in the paper has been performed by the authors, unless clearly specified in the text; All authors gave final approval of the version to be published and have contributed to the study; No ethical approval was needed.
Supported by The Basque Government (BIOMICs Research Group, MICROFLUIDICs & BIOMICs Cluster of the University of the Basque Country UPV/EHU), No. IT1633-22.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
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: Marta Arroyo-Izaga, PharmD, Department of Pharmacy and Food Sciences, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Paseo de la Universidad, No. 7, Vitoria-Gasteiz 01006, Araba/Álava, Spain. marta.arroyo@ehu.eus
Received: September 28, 2022
Peer-review started: September 28, 2022
First decision: December 12, 2022
Revised: December 26, 2022
Accepted: February 13, 2023
Article in press: February 13, 2023
Published online: February 21, 2023
Processing time: 145 Days and 19.9 Hours
ARTICLE HIGHLIGHTS
Research background

Colorectal cancer (CRC) is the third most frequent cancer and is responsible for the second-highest mortality rate in cancer patients worldwide. The main factors which may help prevent CRC are those associated with diet, lifestyle, and prevention of metabolic diseases. With regards to the dietary component, one-carbon metabolism-related nutrients have been considered anticarcinogenic and chemotherapeutic agents in the one-carbon metabolic network. However, it is still unclear whether the influence of methyl donor intake is modified by polymorphisms in these epigenetic regulators.

Research motivation

Although screening for early detection of CRC is effective to help decrease the trends in mortality rates, understanding daily life factors is also important to prevent this type of cancer. A better understanding of the molecular basis of CRC could contribute to a better design of future research and better preventive nutritional management in this type of cancer.

Research objectives

In the present work, we reviewed previous studies that have investigated this matter to improve the current understanding of the molecular basis of CRC.

Research methods

A literature search in the Medline database, Reference Citation Analysis (https://www.referencecitationanalysis.com/, an artificial intelligence technology-based open multidisciplinary citation analysis database), and manual reference screening were performed to identify observational studies published from inception to May 2022. A search for relevant keywords and medical subject heading terms related to dietary methyl donors, dietary components that potentially modulate the bioavailability of methyl groups, genetic variants of methyl-metabolizing enzymes, markers of CpG island methylator phenotype and/or microsatellite instability, in combination with keywords related to CRC events was conducted. The present search was developed according to the “PRISMA Statement” guidelines. To evaluate the validity of the individual studies, two reviewers worked independently to determine the quality of the included studies based on the use of the Newcastle-Ottawa scale for case-control or cohort studies.

Research results

A total of fourteen case-control studies and five cohort studies were identified. In total, the case-control studies included 7055 cases and 9032 controls. The cohort studies included 256914 participants, with 1109 cases recorded during follow-up periods that ranged from 7.3 to 22 years. The dietary components that showed a higher association with CRC risk were folate and alcohol. Thus, high folate intake was considered a protective factor, while high alcohol consumption proved to be a risk factor. Several studies have investigated the association between methyl donor nutrients and/or methyl antagonists (e.g., alcohol) and methylenetetrahydrofolate reductase (MTHFR) polymorphisms and have reported significant interactions. In one of those case-control studies, those with the MTHFR 677 TT genotype, who consume low folate diets, had a greater chance of developing CRC than people with the CC or CT genotype. Two other case-control studies reported that MTHFR 677 TT carriers with high (above mean) or adequate folate intake had a low risk of CRC.

Research conclusions

In this systematic review of observational studies, some interactions between MTHFR polymorphisms, methyl donor nutrients (such as folate), and alcohol on CRC risk are suggested. Moreover, some studies show that vitamin B6, niacin, and alcohol may affect CRC risk through not only genetic but also epigenetic regulation.

Research perspectives

This review was not able to clarify which mechanisms underlie the influence of methyl donor nutrients on DNA methylation, as well as the efficacy of methyl uptake, transportation, and the final involvement in methyl-related gene expression. Further prospective studies with large samples and long follow-up periods, as well as clinical trials that consider the long latency period of CRC, are needed to clarify the influence of methyl group donors as epigenetic regulators, with particular emphasis on differences in CRC subsite-specific risk.