MTHFR C677T genetic polymorphism in combination with serum vitamin B 2 , B 12  and aberrant DNA methylation of P16 and P53 genes in esophageal squamous cell carcinoma and esophageal precancerous lesions: a case–control study

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Abstract

Background

The study aimed to explore the associations between the interactions of serum vitamin B ₂ or B ₁₂ levels, aberrant DNA methylation of p16 or p53 and MTHFR C677T polymorphism and the risks of esophageal squamous cell carcinoma (ESCC) and esophageal precancerous lesion (EPL).

Methods

200 ESCC cases, 200 EPL cases and 200 normal controls were matched by age (± 2 years) and gender. Serum vitamin B ₂ and B ₁₂ levels, MTHFR C677T genetic polymorphisms and the methylation status of genes were assessed. Chi square test, one-way analysis of variance and binary logistic regression were performed.

Results

The lowest quartile of both serum vitamin B ₂ and B ₁₂ with TT genotype showed significant increased EPL risk (OR = 4.91, 95% CI 1.31–18.35; OR = 6.88, 95% CI 1.10–42.80). The highest quartile of both serum vitamin B ₂ and B ₁₂ with CC genotype showed significant decreased ESCC risk (OR = 0.16, 95% CI 0.04–0.60; OR = 0.10, 95% CI 0.02–0.46). The ORs of p16 methylation for genotype CT and TT were 1.98 (95% CI 1.01–3.89) and 17.79 (95% CI 2.26–140.22) in EPL, 4.86 (95% CI 2.48–9.50) and 20.40 (95% CI 2.53–164.81) in ESCC, respectively. Similarly, p53 methylation with genotype TT was associated with increased EPL and ESCC risks (OR = 13.28, 95% CI 1.67–105.70; OR = 15.24, 95% CI 1.90–122.62).

Conclusions

The MTHFR C677T genotype and serum vitamin B ₂ or B ₁₂ levels may interact in ways which associated with the EPL and ESCC risks. The gene–gene interaction suggested that aberrant DNA methyaltion of either p16 or p53 combined with T alleles of MTHFR was associated with increased risks of both EPL and ESCC.

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Most cited references 46

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DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status.

Kevin Sinclair, Cinzia Allegrucci, Ravinder Singh … (2007)

A complex combination of adult health-related disorders can originate from developmental events that occur in utero. The periconceptional period may also be programmable. We report on the effects of restricting the supply of specific B vitamins (i.e., B(12) and folate) and methionine, within normal physiological ranges, from the periconceptional diet of mature female sheep. We hypothesized this would lead to epigenetic modifications to DNA methylation in the preovulatory oocyte and/or preimplantation embryo, with long-term health implications for offspring. DNA methylation is a key epigenetic contributor to maintenance of gene silencing that relies on a dietary supply of methyl groups. We observed no effects on pregnancy establishment or birth weight, but this modest early dietary intervention led to adult offspring that were both heavier and fatter, elicited altered immune responses to antigenic challenge, were insulin-resistant, and had elevated blood pressure-effects that were most obvious in males. The altered methylation status of 4% of 1,400 CpG islands examined by restriction landmark genome scanning in the fetal liver revealed compelling evidence of a widespread epigenetic mechanism associated with this nutritionally programmed effect. Intriguingly, more than half of the affected loci were specific to males. The data provide the first evidence that clinically relevant reductions in specific dietary inputs to the methionine/folate cycles during the periconceptional period can lead to widespread epigenetic alterations to DNA methylation in offspring, and modify adult health-related phenotypes.

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A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status.

Simonetta Friso, Sang-Woon Choi, Domenico Girelli … (2002)

DNA methylation, an essential epigenetic feature of DNA that modulates gene expression and genomic integrity, is catalyzed by methyltransferases that use the universal methyl donor S-adenosyl-l-methionine. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methylTHF), the methyl donor for synthesis of methionine from homocysteine and precursor of S-adenosyl-l-methionine. In the present study we sought to determine the effect of folate status on genomic DNA methylation with an emphasis on the interaction with the common C677T mutation in the MTHFR gene. A liquid chromatography/MS method for the analysis of nucleotide bases was used to assess genomic DNA methylation in peripheral blood mononuclear cell DNA from 105 subjects homozygous for this mutation (T/T) and 187 homozygous for the wild-type (C/C) MTHFR genotype. The results show that genomic DNA methylation directly correlates with folate status and inversely with plasma homocysteine (tHcy) levels (P < 0.01). T/T genotypes had a diminished level of DNA methylation compared with those with the C/C wild-type (32.23 vs.62.24 ng 5-methylcytosine/microg DNA, P < 0.0001). When analyzed according to folate status, however, only the T/T subjects with low levels of folate accounted for the diminished DNA methylation (P < 0.0001). Moreover, in T/T subjects DNA methylation status correlated with the methylated proportion of red blood cell folate and was inversely related to the formylated proportion of red blood cell folates (P < 0.03) that is known to be solely represented in those individuals. These results indicate that the MTHFR C677T polymorphism influences DNA methylation status through an interaction with folate status.

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Histological precursors of oesophageal squamous cell carcinoma: results from a 13 year prospective follow up study in a high risk population.

Y Qiao, Guirong Wang, Xiao Sun … (2005)

Oesophageal squamous cell carcinoma (OSCC) has a very poor prognosis, which is largely due to late diagnosis. Successful early detection strategies will require identification of clinically relevant precursor lesions that can be targets for screening and treatment. To identify the clinically relevant histological precursors of OSCC. A cohort of 682 endoscoped patients from a high risk rural population in Linxian, China. Subjects were endoscoped and biopsied at baseline and followed for 13.5 years. We estimated the relative risk of developing OSCC for each of the initial histological diagnoses using Cox proportional hazards regression models. A total of 114 (16.7%) patients developed OSCC during the follow up period. After adjusting for potential confounding factors, relative risks (95% confidence intervals) for incidence of this tumour, by initial histological diagnosis, were: normal 1.0 (reference), oesophagitis 0.8 (0.2-3.2), basal cell hyperplasia 1.9 (0.8-4.5), mild dysplasia 2.9 (1.6-5.2), moderate dysplasia 9.8 (5.3-18.3), severe dysplasia 28.3 (15.3-52.3), and carcinoma in situ 34.4 (16.6-71.4). In this study, squamous dysplasia and carcinoma in situ were the only histological lesions associated with a significantly increased risk of developing OSCC within 13.5 years after endoscopy. There was no evidence that oesophagitis predisposed to this tumour. Increasing grades of dysplasia were strongly associated with increasing risk, indicating that the histological grading was clinically meaningful. The follow up experience of severe dysplasia and carcinoma in situ was equivalent, suggesting that this distinction is not clinically relevant. Documenting these precursor lesions of OSCC should assist in the development of effective prevention, early detection, and treatment strategies for this disease.

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Author and article information

Contributors

Shaokang Wang: shaokangwang@seu.edu.cn

Guiju Sun: gjsun@seu.edu.cn

Journal

Journal ID (nlm-ta): Cancer Cell Int

Journal ID (iso-abbrev): Cancer Cell Int

Title: Cancer Cell International

Publisher: BioMed Central (London )

ISSN (Electronic): 1475-2867

Publication date (Electronic): 12 November 2019

Publication date PMC-release: 12 November 2019

Publication date Collection: 2019

Volume: 19

Electronic Location Identifier: 288

Affiliations

[1 ]ISNI 0000 0004 1761 0489, GRID grid.263826.b, Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, , Southeast University, ; Nanjing, 210009 People’s Republic of China

[2 ]Huai’an District Center for Disease Control and Prevention, Huai’an, 223200 People’s Republic of China

[3 ]ISNI 0000 0004 1758 1008, GRID grid.464489.3, Jiangsu Vocational College of Medicine, ; Yancheng, 224005 People’s Republic of China

[4 ]ISNI 0000 0000 8803 2373, GRID grid.198530.6, Jiangsu Provincial Center for Disease Control and Prevention, ; Nanjing, 210009 People’s Republic of China

Article

Publisher ID: 1012

DOI: 10.1186/s12935-019-1012-x

PMC ID: 6852963

PubMed ID: 31754346

SO-VID: 8ffa076e-66f7-489e-849d-95c664ae7957

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 12 July 2019

Date accepted : 1 November 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81673147

Award ID: 81372985

Award Recipient : Shaokang Wang

Funded by: FundRef http://dx.doi.org/10.13039/501100012226, Fundamental Research Funds for the Central Universities;

Award ID: 2242017K40035

Award Recipient : Shaokang Wang

Funded by: General Program of University Science Research Project of Jiangsu Province

Award ID: 17KJB190001

Award Recipient : Guiling Huang

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: esophageal squamous cell carcinoma,esophageal precancerous lesion,methylenetetrahydrofolate reductase,vitamin b2,vitamin b12,dna methylation

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: esophageal squamous cell carcinoma, esophageal precancerous lesion, methylenetetrahydrofolate reductase, vitamin b2, vitamin b12, dna methylation