THYLENETETRAHYDROFOLATE REDUCTASE GENE POLYMORPHISMS AND SUSCEPTIBILITY TO ESOPHAGEAL CANCER: A CASE-CONTROL STUDY

Overview

Journal Arq Bras Cir Dig

Specialties Gastroenterology
General Surgery

Date 2022 Sep 14

PMID 36102491

Authors

Evelise Pelegrinelli Zaidan

Michele Tatiana Pereira Tomitao

Marina Alessandra Pereira

Marcia Saldanha Kubrusly

Adriana Vaz Safatle-Ribeiro

Flavio Roberto Takeda

Ivan Cecconello

Ulysses Ribeiro Junior

Affiliations

Soon will be listed here.

Abstract

Background: The enzyme methylenetetrahydrofolate reductase is engaged in DNA synthesis through folate metabolism. Inhibiting the activity of this enzyme increases the susceptibility to mutations, and damage and aberrant DNA methylation, which alters the gene expression of tumor suppressors and proto-oncogenes, potential risk factors for esophageal cancer.

Aims: This study aimed to investigate the association between methylenetetrahydrofolate reductase 677C>T and methylenetetrahydrofolate reductase 1298A>C polymorphisms and susceptibility to esophageal cancer, by assessing the distribution of genotypes and haplotypes between cases and controls, as well as to investigate the association of polymorphisms with clinical and epidemiological characteristics and survival.

Methods: A total of 109 esophageal cancer patients who underwent esophagectomy were evaluated, while 102 subjects constitute the control group. Genomic DNA was isolated from the peripheral blood buffy coat followed by amplification by polymerase chain reaction and real-time analysis. Logistic regression was used to assess associations between polymorphisms and the risk of developing esophageal cancer.

Results: There was no association for methylenetetrahydrofolate reductase 677C>T and methylenetetrahydrofolate reductase 1298A>C polymorphisms and haplotypes, with esophageal cancer susceptibility. Esophageal cancer patients carrying methylenetetrahydrofolate reductase 677TT polymorphism had higher risk of death from the disease. For polymorphic homozygote TT genotype, the risk of death significantly increased compared to wild-type genotype methylenetetrahydrofolate reductase 677CC (reference) cases (p=0.045; RR=2.22, 95%CI 1.02-4.83).

Conclusions: There was no association between methylenetetrahydrofolate reductase 677C>T and methylenetetrahydrofolate reductase 1298A>C polymorphisms and esophageal cancer susceptibility risk. Polymorphic homozygote genotype methylenetetrahydrofolate reductase 677TT was associated with higher risk of death after surgical treatment for esophageal cancer.

References

Canova C, Hashibe M, Simonato L, Nelis M, Metspalu A, Lagiou P . Genetic associations of 115 polymorphisms with cancers of the upper aerodigestive tract across 10 European countries: the ARCAGE project. Cancer Res. 2009; 69(7):2956-65. DOI: 10.1158/0008-5472.CAN-08-2604. View

Miao X, Xing D, Tan W, Qi J, Lu W, Lin D . Susceptibility to gastric cardia adenocarcinoma and genetic polymorphisms in methylenetetrahydrofolate reductase in an at-risk Chinese population. Cancer Epidemiol Biomarkers Prev. 2002; 11(11):1454-8. View

Galbiatti A, Ruiz M, Maniglia J, Raposo L, Pavarino-Bertelli E, Goloni-Bertollo E . Head and neck cancer: genetic polymorphisms and folate metabolism. Braz J Otorhinolaryngol. 2012; 78(1):132-9. PMC: 9443880. DOI: 10.1590/s1808-86942012000100021. View

Lu C, Xie H, Wang F, Shen H, Wang J . Diet folate, DNA methylation and genetic polymorphisms of MTHFR C677T in association with the prognosis of esophageal squamous cell carcinoma. BMC Cancer. 2011; 11:91. PMC: 3059302. DOI: 10.1186/1471-2407-11-91. View

Lewis S, Davey Smith G . Alcohol, ALDH2, and esophageal cancer: a meta-analysis which illustrates the potentials and limitations of a Mendelian randomization approach. Cancer Epidemiol Biomarkers Prev. 2005; 14(8):1967-71. DOI: 10.1158/1055-9965.EPI-05-0196. View

Willett W . Diet and cancer: one view at the start of the millennium. Cancer Epidemiol Biomarkers Prev. 2001; 10(1):3-8. View

Yang C, Matsuo K, Ito H, Shinoda M, Hatooka S, Hirose K . Gene-environment interactions between alcohol drinking and the MTHFR C677T polymorphism impact on esophageal cancer risk: results of a case-control study in Japan. Carcinogenesis. 2005; 26(7):1285-90. DOI: 10.1093/carcin/bgi076. View

Lubin J, Cook M, Pandeya N, Vaughan T, Abnet C, Giffen C . The importance of exposure rate on odds ratios by cigarette smoking and alcohol consumption for esophageal adenocarcinoma and squamous cell carcinoma in the Barrett's Esophagus and Esophageal Adenocarcinoma Consortium. Cancer Epidemiol. 2012; 36(3):306-16. PMC: 3489030. DOI: 10.1016/j.canep.2012.03.001. View

Larsson S, Giovannucci E, Wolk A . Folate intake, MTHFR polymorphisms, and risk of esophageal, gastric, and pancreatic cancer: a meta-analysis. Gastroenterology. 2006; 131(4):1271-83. DOI: 10.1053/j.gastro.2006.08.010. View

10.

Liu Y, Wang B, Wan M, Tang W, Huang F, Li C . Meta-analysis of the relationship between the Metholenetetrahydrofolate reductase C677T genetic polymorphism, folate intake and esophageal cancer. Asian Pac J Cancer Prev. 2011; 12(1):247-52. View

11.

Cheng C, Kuo I, Alakus H, Frazer K, Harismendy O, Wang Y . Network-based analysis identifies epigenetic biomarkers of esophageal squamous cell carcinoma progression. Bioinformatics. 2014; 30(21):3054-61. PMC: 4609006. DOI: 10.1093/bioinformatics/btu433. View

12.

Langevin S, Lin D, Matsuo K, Gao C, Takezaki T, Stolzenberg-Solomon R . Review and pooled analysis of studies on MTHFR C677T polymorphism and esophageal cancer. Toxicol Lett. 2008; 184(2):73-80. PMC: 3512563. DOI: 10.1016/j.toxlet.2008.09.003. View

13.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

14.

Jing C, Huang Z, Duan Y, Xiao X, Zhang R, Jiang J . Folate intake, methylenetetrahydrofolate reductase polymorphisms in association with the prognosis of esophageal squamous cell carcinoma. Asian Pac J Cancer Prev. 2012; 13(2):647-51. DOI: 10.7314/apjcp.2012.13.2.647. View

15.

Druesne-Pecollo N, Tehard B, Mallet Y, Gerber M, Norat T, Hercberg S . Alcohol and genetic polymorphisms: effect on risk of alcohol-related cancer. Lancet Oncol. 2009; 10(2):173-80. DOI: 10.1016/S1470-2045(09)70019-1. View

16.

Eads C, Nickel A, Laird P . Complete genetic suppression of polyp formation and reduction of CpG-island hypermethylation in Apc(Min/+) Dnmt1-hypomorphic Mice. Cancer Res. 2002; 62(5):1296-9. View

17.

Butler L, Sinha R, Millikan R, Martin C, Newman B, Gammon M . Heterocyclic amines, meat intake, and association with colon cancer in a population-based study. Am J Epidemiol. 2003; 157(5):434-45. DOI: 10.1093/aje/kwf221. View

18.

Brookes A . The essence of SNPs. Gene. 1999; 234(2):177-86. DOI: 10.1016/s0378-1119(99)00219-x. View

19.

Barrett J, Fry B, Maller J, Daly M . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2004; 21(2):263-5. DOI: 10.1093/bioinformatics/bth457. View

20.

Napier K, Scheerer M, Misra S . Esophageal cancer: A Review of epidemiology, pathogenesis, staging workup and treatment modalities. World J Gastrointest Oncol. 2014; 6(5):112-20. PMC: 4021327. DOI: 10.4251/wjgo.v6.i5.112. View