Association of Human Methionine Synthase-A2756G Transition With Prostate Cancer: A Case-Control Study and in Silico Analysis


Methionine synthase (MTR) is one of the key enzymes of folate pathway, which play a key role in the construction, repair, and methylation of DNA. In this study, an association of MTR A2756G gene transition with prostate cancer in men populations of Kashan-Iran was investigated by a case-control study and an in silico analysis. The 200 samples including 100 patients with prostate cancer, as case group and 100 healthy men, as control group included in this study. MTR-A2756G genotyping was performed by PCR-RFLP technique. Some in silico tools used to evaluate the effects of A2756G transition on the structure and function of MTR. Results showed that the AG genotype (OR: 2.4014, 95% CI: 1.3216-4.3636, P=0.0040), and GG genotype (OR: 3.6324, 95% CI: 1.2629-10.4475, P=0.0167) and G allele (OR: 2.0120, 95% CI: 1.3098-3.0905, P=0.0014) were associated with prostate cancer. In silico analysis showed that polymorphisms of the enzyme protein might change properties of MTR such as relative mutability and flexibility, which leads to alteration of stability and function of the enzyme. Based on the results, an MTR-A2756G polymorphism which changes activity and stability of the methionine synthase associated with prostate cancer in men. It is a preliminary study and is presenting data for future comprehensive study for making a clinical conclusion that this gene transition is a biomarker for susceptibility to prostate cancer.

Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90.

Muslumanoglu MH, Tepeli E, Demir S, Uludag A, Uzun D, Atli E, et al. The analysis of the relationship between A1298C and C677T polymorphisms of the MTHFR gene with prostate cancer in Eskisehir population. Genet Test Mol Biomarkers 2009;13:641-5.

Kim KC, Simonetta F, Choi SW. DNA methylation, an epigenetic mechanism connecting folate to healthy embryonic development and aging. J Nutr Biochem 2009;20:917–26.

Brody LC, Baker PJ, Chines PS, Musick A, Molloy AM, Swanson DA, et al. Methionine synthase: high-resolution mapping of the human gene and evaluation as a candidate locus for neural tube defects. Mol Genet Metab 1999;67:324-33.

Chen LH, Liu ML, Hwang HY, Chen LS, Korenberg J, Shane B. Human methionine synthase. cDNA cloning, gene localization, and expression. J Biol Chem 1997;272:3628-34.

Goulding CW, Postigo D, Matthews RG. Cobalamin-dependent methionine synthase is a modular protein with distinct regions for binding homocysteine, methyltetrahydrofolate, cobalamin, and adenosylmethionine. Biochemistry 1997;36:8082-91.

Leclerc D, Wilson A, Dumas R, Gafuik C, Song D, Watkins D, et al. Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria. Proc Natl Acad Sci 1998;95:3059-64.

Collin SM, Metcalfe C, Zuccolo L, Lewis SJ, Chen L, Cox A, et al. Association of Folate-Pathway Gene Polymorphisms with the Risk of Prostate Cancer: a Population-Based Nested Case-Control Study, Systematic Review, and Meta-analysis. Cancer Epidemiol Biomarkers Prev 2009;18:2528-39.

Matsuo K, Suzuki R, Hamajima N, Ogura M, Kagami Y, Taji H, et al. Association between polymorphisms of folateand methionine-metabolizing enzymes and susceptibility to malignant lymphoma. Blood 2001;97:3205-09.

Goode EL, Potter JD, Bigler J, Ulrich CM. Methionine synthase D919G polymorphism, folate metabolism, and colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev 2004;13:157-62.

Paz MF, Avila S, Fraga MF, Pollan M, Capella G, Peinado MA, et al. Germ-line variants in methyl-group metabolism genes and susceptibility to DNA methylation in normal tissues and human primary tumors. Cancer Res 2002;62:4519-24.

Klerk M, Lievers KJ, Kluijtmans LA, Blom HJ, den Heijer M, Schouten EG, et al. The 2756A >G variant in the gene encoding methionine synthase: its relation with plasma homocysteine levels and risk of coronary heart disease in a Dutch case-control study. Thromb Res 2003;110:87–91.

Chang SC, Chang PY, Butler B, Goldstein BY, Mu L, Cai L, et al. Single nucleotide polymorphisms of one-carbon metabolism and cancers of the esophagus, stomach, and liver in a Chinese population. Plos one 2014;9:e109235.

Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16:1215.

Wang R, Zheng Y, Huang JY, Zhang AQ, Zhou YH, Wang JN. Folate intake, serum folate levels, and prostate cancer risk: a meta-analysis of prospective studies. BMC Public Health 2014;14:1.

Center MM, Jemal A, Lortet-Tieulent J, Ward E, Ferlay J, Brawley O, et al. International Variation in Prostate Cancer Incidence and Mortality Rates. Eur Urol 2012;61:1079-92.

Larkin SE, Holmes S, Cree IA, Walker T, Basketter V, Bickers B, et al. Identification of markers of prostate cancer progression using candidate gene expression. Br J Cancer 2012;106:157-65.

Marchal C, Redondo M, Reyes-Engel A, Perea-Milla E, Gaitan MJ, Machuca J, et al. Association between polymorphisms of folate-metabolizing enzymes and risk of prostate cancer. Eur J Surg Oncol 2008;34:805-10.

Cai D, Ning L, Pan C, Liu X, Bu R, Chen X, et al. Association of polymorphisms in folate metabolic genes and prostate cancer risk: a case-control study in a Chinese population. J Genet 2010;89:263-67.

Donkena KV, Yuan H, Young CY. Vitamin Bs, one carbon metabolism and prostate cancer. Mini Rev Med Chem 2010;10:1385-92.

Blount BC, Mack MM, Wehr CM, MacGregor JT, Hiatt RA, Wang G, et al. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage. J Med Sci 1997;94:3290-95.

Shannon J, Phoutrides E, Palma A, Farris P, Peters L, Forester A, et al. Folate intake and prostate cancer risk: a case-control study. Nutr Cancer 2009;61:617-28.

Hultdin J, Guelpen BV, Bergh A, Hallmans G, Stattin P. Plasma folate, vitamin B12, and homocysteine and prostate cancer risk: a prospective study. Int J Cancer 2005;113:819-24.

Jackson MD, Tulloch-Reid MK, McFarlane-Anderson N, Watson A, Seers V, Bennett FI, et al. Complex interaction between serum folate levels and genetic polymorphisms in folate pathway genes: biomarkers of prostate cancer aggressiveness. Genes Nutr


Ma E, Iwasaki M, Junko I, Hamada GS, Nishimoto IN, Carvalho SM, et al. Dietary intake of folate, vitamin B6, and vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Brazilian women. BMC Cancer 2009;9:1-10.

Schalinske KL, Nieman KM. Disruption of methyl group metabolism by ethanol. Nutr Rev 2005;63:387-91.

Majumdar S, Buckles E, Estrada J, Koochekpour S. Aberrant DNA methylation and prostate cancer. Curr Genomics 2011;12:486-505.

Lin X, Nelson WG. Methyl-CpG-binding domain protein-2 mediates transcriptional repression associated with hypermethylated GSTP1 CpG islands in MCF-7 breast cancer cells. Cancer Res 2003;63:498-504.

Nikzad H, Karimian M, Sareban K, Khoshsokhan M, Colagar AH. MTHFR-Ala222Val and male infertility: a study in Iranian men, an updated meta-analysis and an in silico-analysis. Reprod Biomed Online 2015;31:668-80.

Karimian M, Hosseinzadeh Colagar A. Association of C677T transition of the human methylenetetrahydrofolate reductase (MTHFR) gene with male infertility. Reprod Fertil Dev 2016;28:785-94.

Bu ZI, Callaway DJ. Proteins move! Protein dynamics and long-range allostery in cell signaling. Adv Protein Chem Struct Biol 2011;83:163-221.

Huang F, Nau WM. A conformational flexibility scale for amino acids in peptides. Angew. Chem 2003;115:2371-74.

Pavelka A, Chovancova E, Damborsky J. HotSpot Wizard: a web server for identification of hot spots in protein engineering. Nucleic Acids Res 2009;37:376-83.

Karimian M, Hosseinzadeh Colagar A. Methionine synthase A2756G transition might be a risk factor for male infertility: Evidences from seven case-control studies. Mol Cell Endocrinol 2016;425:1-10.

IssueVol 55, No 5 (2017) QRcode
Prostate cancer MTR gene A2756G transition PCR-RFLP

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How to Cite
Ebrahimi A, Hosseinzadeh Colagar A, Karimian M. Association of Human Methionine Synthase-A2756G Transition With Prostate Cancer: A Case-Control Study and in Silico Analysis. Acta Med Iran. 55(5):297-303.