Abstract
Methionine synthase reductase (MTRR) gene is involved in tumorigenesis by regulating DNA methylation through activation of methionine synthase (MTR). MTRR is polymorphic at nucleotide 66 (A-to-G) and the resulting variant enzyme has a lower affinity for MTR. The reported associations of MTRR A66G polymorphism with cancer risk are contradictory. Therefore, we performed a meta-analysis to better assess the associations, including 18,661 cases and 27,678 controls from 35 studies. Crude ORs with 95% CIs were used to assess the strength of association between the MTRR A66G polymorphism and cancer risk. The pooled ORs were performed for homozygote model (GG vs. AA), heterozygote model (GG vs. GA), recessive genetic model (GG vs. GA + AA), and dominant genetic model (GG + GA vs. AA), respectively. Overall, results indicated that the G allele and GG variant genotypes were associated with a significantly increased cancer risk (G vs. A: OR, 1.039; 95% CI, 1.009–1.078; homozygote model: OR, 1.094; 95% CI, 1.006–1.191). In subgroup analysis by ethnicity, significant increased risks were found among Asians with G allele (G vs. A: OR, 1.063; 95% CI, 1.011–1.119; homozygote model: OR, 1.189; 95% CI, 1.055–1.341; recessive model: OR, 1.197; 95% CI, 1.068–1.341). For stratification analysis, the cancer types with fewer than three studies were categorized into “other cancers”, and the results indicated that there was a significant elevated cancer risk in “other cancers” in all genetic models, not in colorectal cancer, lymphoid leukemia or breast cancer. In summary, our study suggests that the MTRR A66G polymorphism is a potential biomarker for cancer risk.
Similar content being viewed by others
References
Stern LL, Mason JB, Selhub J, Choi SW (2000) Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene. Cancer Epidemiol Biomarkers Prev 9(8):849–853
Ma J, Stampfer MJ, Christensen B, Giovannucci E, Hunter DJ, Chen J, Willett WC, Selhub J, Hennekens CH, Gravel R, Rozen R (1999) A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 8(9):825–829
Olteanu H, Munson T, Banerjee R (2002) Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase. Biochemistry 41(45):13378–13385
Gaughan DJ, Kluijtmans LA, Barbaux S, McMaster D, Young IS, Yarnell JW, Evans A, Whitehead AS (2001) The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations. Atherosclerosis 157(2):451–456
Geisel J, Zimbelmann I, Schorr H, Knapp JP, Bodis M, Hubner U, Herrmann W (2001) Genetic defects as important factors for moderate hyperhomocysteinemia. Clin Chem Lab Med 39(8):698–704. doi:10.1515/CCLM.2001.115
O’Leary VB, Parle-McDermott A, Molloy AM, Kirke PN, Johnson Z, Conley M, Scott JM, Mills JL (2002) MTRR and MTHFR polymorphism: link to Down syndrome? Am J Med Genet 107(2):151–155. doi:10.1002/ajmg.10121
Matsuo K, Hamajima N, Hirai T, Kato T, Inoue M, Takezaki T, Tajima K (2002) Methionine synthase reductase gene A66G Polymorphism is associated with risk of colorectal cancer. Asian Pac J Cancer Prev 3(4):353–359
Le Marchand L, Donlon T, Hankin JH, Kolonel LN, Wilkens LR, Seifried A (2002) B-vitamin intake, metabolic genes, and colorectal cancer risk (United States). Cancer Causes Control 13(3):239–248
Gast A, Bermejo JL, Flohr T, Stanulla M, Burwinkel B, Schrappe M, Bartram CR, Hemminki K, Kumar R (2007) Folate metabolic gene polymorphisms and childhood acute lymphoblastic leukemia: a case-control study. Leukemia 21(2):320–325. doi:10.1038/sj.leu.2404474
Koppen IJ, Hermans FJ, Kaspers GJ (2010) Folate related gene polymorphisms and susceptibility to develop childhood acute lymphoblastic leukaemia. Br J Haematol 148(1):3–14. doi:10.1111/j.1365-2141.2009.07898.x
Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22(4):719–748
DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188
Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. Br Med J 315(7109):629–634
Brown CA, McKinney KQ, Kaufman JS, Gravel RA, Rozen R (2000) A common polymorphism in methionine synthase reductase increases risk of premature coronary artery disease. J Cardiovasc Risk 7(3):197–200
Feix A, Winkelmayer WC, Eberle C, Sunder-Plassmann G, Fodinger M (2004) Methionine synthase reductase MTRR 66A > G has no effect on total homocysteine, folate, and Vitamin B12 concentrations in renal transplant patients. Atherosclerosis 174(1):43–48. doi:10.1016/j.atherosclerosis.2003.12.036
Jones PA, Laird PW (1999) Cancer epigenetics comes of age. Nat Genet 21(2):163–167. doi:10.1038/5947
Kwak SY, Kim UK, Cho HJ, Lee HK, Kim HJ, Kim NK, Hwang SG (2008) Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) gene polymorphisms as risk factors for hepatocellular carcinoma in a Korean population. Anticancer Res 28(5A):2807–2811
Stolzenberg-Solomon RZ, Qiao YL, Abnet CC, Ratnasinghe DL, Dawsey SM, Dong ZW, Taylor PR, Mark SD (2003) Esophageal and gastric cardia cancer risk and folate- and vitamin B(12)-related polymorphisms in Linxian, China. Cancer Epidemiol Biomarkers Prev 12(11 Pt 1):1222–1226
Suzuki T, Matsuo K, Hasegawa Y, Hiraki A, Wakai K, Hirose K, Saito T, Sato S, Ueda R, Tajima K (2007) One-carbon metabolism-related gene polymorphisms and risk of head and neck squamous cell carcinoma: case-control study. Cancer Sci 98(9):1439–1446. doi:10.1111/j.1349-7006.2007.00533.x
Moore LE, Malats N, Rothman N, Real FX, Kogevinas M, Karami S, Garcia-Closas R, Silverman D, Chanock S, Welch R, Tardon A, Serra C, Carrato A, Dosemeci M, Garcia-Closas M (2007) Polymorphisms in one-carbon metabolism and trans-sulfuration pathway genes and susceptibility to bladder cancer. Int J Cancer 120(11):2452–2458. doi:10.1002/ijc.22565
Yong D, QingQing W, Hua L, Yang LX, QingLing Z, Ying H, QiaoJing Q, HanChao S (2006) Association of uteroglobin G38A polymorphism with IgA nephropathy: a meta-analysis. Am J Kidney Dis 48(1):1–7. doi:10.1053/j.ajkd.2006.03.048
Koushik A, Kraft P, Fuchs CS, Hankinson SE, Willett WC, Giovannucci EL, Hunter DJ (2006) Nonsynonymous polymorphisms in genes in the one-carbon metabolism pathway and associations with colorectal cancer. Cancer Epidemiol Biomarkers Prev 15(12):2408–2417. doi:10.1158/1055-9965.EPI-06-0624
Theodoratou E, Farrington SM, Tenesa A, McNeill G, Cetnarskyj R, Barnetson RA, Porteous ME, Dunlop MG, Campbell H (2008) Dietary vitamin B6 intake and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev 17(1):171–182. doi:10.1158/1055-9965.EPI-07-0621
Otani T, Iwasaki M, Hanaoka T, Kobayashi M, Ishihara J, Natsukawa S, Shaura K, Koizumi Y, Kasuga Y, Yoshimura K, Yoshida T, Tsugane S (2005) Folate, vitamin B6, vitamin B12, and vitamin B2 intake, genetic polymorphisms of related enzymes, and risk of colorectal cancer in a hospital-based case-control study in Japan. Nutr Cancer 53(1):42–50. doi:10.1207/s15327914nc5301_5
Steck SE, Keku T, Butler LM, Galanko J, Massa B, Millikan RC, Sandler RS (2008) Polymorphisms in methionine synthase, methionine synthase reductase and serine hydroxymethyltransferase, folate and alcohol intake, and colon cancer risk. J Nutrigenet Nutrigenomics 1(4):196–204. doi:10.1159/000136651
Hazra A, Wu K, Kraft P, Fuchs CS, Giovannucci EL, Hunter DJ (2007) Twenty-four non-synonymous polymorphisms in the one-carbon metabolic pathway and risk of colorectal adenoma in the Nurses’ Health Study. Carcinogenesis 28(7):1510–1519. doi:10.1093/carcin/bgm062
Kim HN, Kim YK, Lee IK, Yang DH, Lee JJ, Shin MH, Park KS, Choi JS, Park MR, Jo DY, Won JH, Kwak JY, Kim HJ (2009) Association between polymorphisms of folate-metabolizing enzymes and hematological malignancies. Leuk Res 33(1):82–87. doi:10.1016/j.leukres.2008.07.026
Gemmati D, Ongaro A, Scapoli GL, Della Porta M, Tognazzo S, Serino ML, Di Bona E, Rodeghiero F, Gilli G, Reverberi R, Caruso A, Pasello M, Pellati A, De Mattei M (2004) Common gene polymorphisms in the metabolic folate and methylation pathway and the risk of acute lymphoblastic leukemia and non-Hodgkin’s lymphoma in adults. Cancer Epidemiol Biomarkers Prev 13(5):787–794
Petra BG, Janez J, Vita D (2007) Gene-gene interactions in the folate metabolic pathway influence the risk for acute lymphoblastic leukemia in children. Leuk Lymphoma 48(4):786–792. doi:10.1080/10428190601187711
Gra OA, Glotov AS, Kozhekbaeva Z, Makarova OV, Nasedkina TV (2008) Genetic polymorphism in GST, NAT2, and MTRR and susceptibility to childhood acute leukemia. Mol Biol (Mosk) 42(2):214–225
de Jonge R, Tissing WJ, Hooijberg JH, Jansen G, Kaspers GJ, Lindemans J, Peters GJ, Pieters R (2009) Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia. Blood 113(10):2284–2289. doi:10.1182/blood-2008-07-165928
Lissowska J, Gaudet MM, Brinton LA, Chanock SJ, Peplonska B, Welch R, Zatonski W, Szeszenia-Dabrowska N, Park S, Sherman M, Garcia-Closas M (2007) Genetic polymorphisms in the one-carbon metabolism pathway and breast cancer risk: a population-based case-control study and meta-analyses. Int J Cancer 120(12):2696–2703. doi:10.1002/ijc.22604
Shrubsole MJ, Gao YT, Cai Q, Shu XO, Dai Q, Jin F, Zheng W (2006) MTR and MTRR polymorphisms, dietary intake, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 15(3):586–588. doi:10.1158/1055-9965.EPI-05-0576
Suzuki T, Matsuo K, Hirose K, Hiraki A, Kawase T, Watanabe M, Yamashita T, Iwata H, Tajima K (2008) One-carbon metabolism-related gene polymorphisms and risk of breast cancer. Carcinogenesis 29(2):356–362. doi:10.1093/carcin/bgm295
Kotsopoulos J, Zhang WW, Zhang S, McCready D, Trudeau M, Zhang P, Sun P, Narod SA (2008) Polymorphisms in folate metabolizing enzymes and transport proteins and the risk of breast cancer. Breast Cancer Res Treat 112(3):585–593. doi:10.1007/s10549-008-9895-6
Xu X, Gammon MD, Zhang H, Wetmur JG, Rao M, Teitelbaum SL, Britton JA, Neugut AI, Santella RM, Chen J (2007) Polymorphisms of one-carbon-metabolizing genes and risk of breast cancer in a population-based study. Carcinogenesis 28(7):1504–1509. doi:10.1093/carcin/bgm061
Sangrajrang S, Sato Y, Sakamoto H, Ohnami S, Khuhaprema T, Yoshida T (2010) Genetic polymorphisms in folate and alcohol metabolism and breast cancer risk: a case-control study in Thai women. Breast Cancer Res Treat. doi:10.1007/s10549-010-0804-4
Rouissi K, Ouerhani S, Oliveira E, Marrakchi R, Cherni L, Ben Othman F, Ben Slama MR, Sfaxi M, Ayed M, Chebil M, Amorim A, Prata MJ, Benammar Elgaaied A (2009) Polymorphisms in one-carbon metabolism pathway genes and risk for bladder cancer in a Tunisian population. Cancer Genet Cytogenet 195(1):43–53. doi:10.1016/j.cancergencyto.2009.06.007
Kim HN, Kim YK, Lee IK, Lee JJ, Yang DH, Park KS, Choi JS, Park MR, Jo DY, Kim HJ (2007) Polymorphisms involved in the folate metabolizing pathway and risk of multiple myeloma. Am J Hematol 82(9):798–801. doi:10.1002/ajh.20967
Lima CS, Ortega MM, Ozelo MC, Araujo RC, De Souza CA, Lorand-Metze I, Annichino-Bizzacchi JM, Costa FF (2008) Polymorphisms of methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), and thymidylate synthase (TYMS) in multiple myeloma risk. Leuk Res 32(3):401–405. doi:10.1016/j.leukres.2007.06.001
Kim HN, Lee IK, Kim YK, Tran HT, Yang DH, Lee JJ, Shin MH, Park KS, Shin MG, Choi JS, Kim HJ (2008) Association between folate-metabolizing pathway polymorphism and non-Hodgkin lymphoma. Br J Haematol 140(3):287–294. doi:10.1111/j.1365-2141.2007.06893.x
Zhang FF, Terry MB, Hou L, Chen J, Lissowska J, Yeager M, Zatonski W, Chanock S, Morabia A, Chow WH (2007) Genetic polymorphisms in folate metabolism and the risk of stomach cancer. Cancer Epidemiol Biomarkers Prev 16(1):115–121. doi:10.1158/1055-9965.EPI-06-0513
Zhang Z, Shi Q, Liu Z, Sturgis EM, Spitz MR, Wei Q (2005) Polymorphisms of methionine synthase and methionine synthase reductase and risk of squamous cell carcinoma of the head and neck: a case-control analysis. Cancer Epidemiol Biomarkers Prev 14(5):1188–1193. doi:10.1158/1055-9965.EPI-04-0501
Suzuki T, Matsuo K, Hiraki A, Saito T, Sato S, Yatabe Y, Mitsudomi T, Hida T, Ueda R, Tajima K (2007) Impact of one-carbon metabolism-related gene polymorphisms on risk of lung cancer in Japan: a case control study. Carcinogenesis 28(8):1718–1725. doi:10.1093/carcin/bgm104
Shi Q, Zhang Z, Li G, Pillow PC, Hernandez LM, Spitz MR, Wei Q (2005) Polymorphisms of methionine synthase and methionine synthase reductase and risk of lung cancer: a case-control analysis. Pharmacogenet Genomics 15(8):547–555
Bethke L, Webb E, Murray A, Schoemaker M, Feychting M, Lonn S, Ahlbom A, Malmer B, Henriksson R, Auvinen A, Kiuru A, Salminen T, Johansen C, Christensen HC, Muir K, McKinney P, Hepworth S, Dimitropoulou P, Lophatananon A, Swerdlow A, Houlston R (2008) Functional polymorphisms in folate metabolism genes influence the risk of meningioma and glioma. Cancer Epidemiol Biomarkers Prev 17(5):1195–1202. doi:10.1158/1055-9965.EPI-07-2733
Suzuki T, Matsuo K, Sawaki A, Mizuno N, Hiraki A, Kawase T, Watanabe M, Nakamura T, Yamao K, Tajima K, Tanaka H (2008) Alcohol drinking and one-carbon metabolism-related gene polymorphisms on pancreatic cancer risk. Cancer Epidemiol Biomarkers Prev 17(10):2742–2747. doi:10.1158/1055-9965.EPI-08-0470
Marchal C, Redondo M, Reyes-Engel A, Perea-Milla E, Gaitan MJ, Machuca J, Diaz F, Caballero J, Carnero J (2008) Association between polymorphisms of folate-metabolizing enzymes and risk of prostate cancer. Eur J Surg Oncol 34(7):805–810. doi:10.1016/j.ejso.2007.09.008
Tong SY, Lee JM, Song ES, Lee KB, Kim MK, Yun YM, Lee JK, Son SK, Lee JP, Kim JH, Hur SY, Kwon YI (2010) The effects of polymorphisms in methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) on the risk of cervical intraepithelial neoplasia and cervical cancer in Korean women. Cancer Causes Control 21(1):23–30. doi:10.1007/s10552-009-9430-z
Acknowledgments
The project was supported by The National High Technology R&D Program of China [2009AA022701] and The National Basic Research Program of China [2010CB534901]. We would like to thank the anonymous reviewer and the editor for their constructive comments on revising this manuscript.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Additional information
Dong Han and Chao Shen contributed equally to this work.
Rights and permissions
About this article
Cite this article
Han, D., Shen, C., Meng, X. et al. Methionine synthase reductase A66G polymorphism contributes to tumor susceptibility: evidence from 35 case–control studies. Mol Biol Rep 39, 805–816 (2012). https://doi.org/10.1007/s11033-011-0802-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-011-0802-6