title: The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and tumor risk: evidence from 134 case-control studies.
abstract: Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism, which is essential for DNA synthesis and methylation. Genetic variations in the MTHFR gene seem to contribute to a decreased activity of MTHFR, ultimately confer increased susceptibility to cancer. As the most extensively studied polymorphism, MTHFR C677T polymorphism was shown to contribute to cancer susceptibility but the results were inconsistent. The authors performed a meta-analysis including 134 studies (46,207 cases and 69,160 controls) to address the issue. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to assess the association. Overall, a significant elevated risk of cancer was associated with the MTHFR C677T polymorphism in T-allele versus C-allele comparison (OR = 1.06, 95% CI 1.02-1.11, P(heterogeneity) < 0.001), homozygote model (OR = 1.08, 95% CI 1.01-1.17, P(heterogeneity) < 0.001) and dominant model (OR = 1.05, 95% CI 1.00-1.10, P(heterogeneity) < 0.001). In the stratified analyses, significantly increased cancer risks were indicated among Asians in all genetic models except for heterozygote model. Further analysis revealed that C677T was significantly associated with an increased risk of esophageal and stomach cancer. This meta-analysis supports an association between the MTHFR C677T polymorphism and increased risk of esophageal and stomach cancer, especially among Asians. Additionally, more high-quality studies and that the covariates responsible for heterogeneity should be controlled to obtain a more conclusive response about the function of MTHFR C677T in cancer.
authors.affiliation: Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Tang
authors.forename: Shang-Qian
authors.initials: SQ
authors.lastname: Wang
authors.forename: Bian-Jiang
authors.initials: BJ
authors.lastname: Liu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Cao
authors.forename: Bing-Jie
authors.initials: BJ
authors.lastname: Li
authors.forename: Peng-Chao
authors.initials: PC
authors.lastname: Li
authors.forename: Yong-Fei
authors.initials: YF
authors.lastname: Li
authors.forename: Chao
authors.initials: C
authors.lastname: Qin
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000483:Alleles; D044466:Asian People; D016022:Case-Control Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D009369:Neoplasms / Q000145:classification / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D044465:White People
chemical_list: C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)
references.citation: Cancer Epidemiol Biomarkers Prev. 2002 Dec;11(12):1611-21
references.pmid: 12496052
references.citation: Int J Cancer. 2005 May 20;115(1):131-6
references.pmid: 15688408
references.citation: Tumour Biol. 2010 Jan;31(1):23-32
references.pmid: 20237899
references.citation: Asian Pac J Cancer Prev. 2011;12(1):247-52
references.pmid: 21517266
references.citation: Ann Intern Med. 1997 Nov 1;127(9):820-6
references.pmid: 9382404
references.citation: Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12810-5
references.pmid: 10536004
references.citation: Clin Biochem. 2007 Sep;40(13-14):981-5
references.pmid: 17573062
references.citation: Cancer Epidemiol Biomarkers Prev. 2002 Nov;11(11):1454-8
references.pmid: 12433726
references.citation: Asian Pac J Cancer Prev. 2011;12(7):1833-5
references.pmid: 22126575
references.citation: Mol Biol Rep. 2011 Nov;38(8):4893-901
references.pmid: 21161404
references.citation: Cancer Res. 1997 Mar 15;57(6):1098-102
references.pmid: 9067278
references.citation: Eur J Nutr. 2009 Aug;48(5):269-76
references.pmid: 19288150
references.citation: Anticancer Res. 2006 May-Jun;26(3B):2445-9
references.pmid: 16821630
references.citation: Cell Biochem Funct. 2007 Jul-Aug;25(4):419-22
references.pmid: 16927418
references.citation: World J Gastroenterol. 2008 Dec 7;14(45):6986-92
references.pmid: 19058336
references.citation: Genet Test Mol Biomarkers. 2012 Jul;16(7):780-4
references.pmid: 22536880
references.citation: Cancer Causes Control. 2007 Aug;18(6):665-75
references.pmid: 17503006
references.citation: ORL J Otorhinolaryngol Relat Spec. 2004;66(5):241-5
references.pmid: 15583437
references.citation: J Nutr. 2002 Apr;132(4):762-7
references.pmid: 11925474
references.citation: Cancer Epidemiol Biomarkers Prev. 2009 Mar;18(3):998-1002
references.pmid: 19240236
references.citation: Genet Test Mol Biomarkers. 2011 Jan-Feb;15(1-2):5-10
references.pmid: 21117954
references.citation: Breast Cancer Res Treat. 2008 Feb;107(3):459-60
references.pmid: 17453338
references.citation: Food Chem Toxicol. 2010 Jul;48(7):1881-5
references.pmid: 20417243
references.citation: Cancer Epidemiol Biomarkers Prev. 2000 Aug;9(8):849-53
references.pmid: 10952104
references.citation: Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1140-7
references.pmid: 17548676
references.citation: Exp Mol Med. 2004 Apr 30;36(2):116-21
references.pmid: 15150439
references.citation: Cancer Res. 2005 Feb 15;65(4):1606-14
references.pmid: 15735051
references.citation: Anticancer Res. 2004 Nov-Dec;24(6):3863-8
references.pmid: 15736423
references.citation: Ann Hematol. 2006 Jul;85(7):474-7
references.pmid: 16541270
references.citation: Br J Cancer. 2012 Jun 5;106(12):2016-24
references.pmid: 22669161
references.citation: Genet Mol Res. 2011 Jun 21;10(2):1200-10
references.pmid: 21732284
references.citation: Mutagenesis. 2011 Jul;26(4):573-81
references.pmid: 21502193
references.citation: Leuk Res. 2009 Jan;33(1):82-7
references.pmid: 18774170
references.citation: Indian J Med Res. 2010 May;131:659-64
references.pmid: 20516537
references.citation: Blood. 2010 May 13;115(19):3923-9
references.pmid: 20101025
references.citation: Int J Gastrointest Cancer. 2001;30(3):105-11
references.pmid: 12540022
references.citation: J Korean Soc Coloproctol. 2011 Apr;27(2):78-82
references.pmid: 21602966
references.citation: Med Oncol. 2012 Sep;29(3):1837-42
references.pmid: 21956592
references.citation: BMC Med Genet. 2011 Feb 22;12:28
references.pmid: 21342495
references.citation: J Pediatr Hematol Oncol. 2010 May;32(4):e148-50
references.pmid: 20445408
references.citation: Cancer Epidemiol Biomarkers Prev. 2005 May;14(5):1198-203
references.pmid: 15894672
references.citation: Cancer Res. 2001 Apr 15;61(8):3272-5
references.pmid: 11309278
references.citation: Int J Cancer. 2007 Mar 1;120(5):1027-35
references.pmid: 17131337
references.citation: Int J Cancer. 2009 Jul 1;125(1):84-90
references.pmid: 19326430
references.citation: Mol Med Rep. 2009 Mar-Apr;2(2):283-9
references.pmid: 21475826
references.citation: In Vivo. 2005 Sep-Oct;19(5):889-93
references.pmid: 16097444
references.citation: Cancer Epidemiol Biomarkers Prev. 2004 Feb;13(2):190-6
references.pmid: 14973091
references.citation: Cancer Sci. 2004 Nov;95(11):908-13
references.pmid: 15546509
references.citation: J Egypt Natl Canc Inst. 2005 Sep;17(3):184-92
references.pmid: 16799656
references.citation: Nat Struct Biol. 1999 Apr;6(4):359-65
references.pmid: 10201405
references.citation: Cancer Epidemiol Biomarkers Prev. 2005 Dec;14(12):2999-3003
references.pmid: 16365025
references.citation: Breast Cancer Res Treat. 2003 Feb;77(3):217-23
references.pmid: 12602921
references.citation: Cancer Epidemiol Biomarkers Prev. 1999 Jun;8(6):513-8
references.pmid: 10385141
references.citation: Cell Biochem Funct. 2007 Jan-Feb;25(1):115-7
references.pmid: 16134079
references.citation: Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4004-9
references.pmid: 11274424
references.citation: Cancer Lett. 2003 Mar 10;191(2):179-85
references.pmid: 12618331
references.citation: Tumour Biol. 2003 Nov-Dec;24(6):286-90
references.pmid: 15004488
references.citation: Cancer Genet Cytogenet. 2009 Nov;195(1):43-53
references.pmid: 19837268
references.citation: Int J Cancer. 2006 Feb 1;118(3):628-32
references.pmid: 16094648
references.citation: Cancer Causes Control. 2007 Mar;18(2):153-63
references.pmid: 17245555
references.citation: Dis Esophagus. 2005;18(3):177-84
references.pmid: 16045580
references.citation: Pharmacogenomics. 2011 Jun;12(6):797-808
references.pmid: 21605004
references.citation: Mol Nutr Food Res. 2006 Aug;50(8):769-74
references.pmid: 16865747
references.citation: Arch Med Res. 2008 Aug;39(6):594-600
references.pmid: 18662591
references.citation: Carcinogenesis. 2004 Sep;25(9):1639-47
references.pmid: 15117811
references.citation: Oncol Rep. 2005 Feb;13(2):355-60
references.pmid: 15643524
references.citation: Carcinogenesis. 2005 Jul;26(7):1285-90
references.pmid: 15790587
references.citation: Gut. 2006 Oct;55(10):1461-6
references.pmid: 16638790
references.citation: Int J Oncol. 2004 Nov;25(5):1465-71
references.pmid: 15492840
references.citation: Int J Cancer. 2006 Feb 15;118(4):991-7
references.pmid: 16152599
references.citation: Cancer Epidemiol Biomarkers Prev. 2004 Jun;13(6):1088-9
references.pmid: 15184272
references.citation: Cancer Lett. 2004 Dec 28;216(2):199-205
references.pmid: 15533596
references.citation: BMJ. 1997 Sep 13;315(7109):629-34
references.pmid: 9310563
references.citation: Carcinogenesis. 2006 Nov;27(11):2295-300
references.pmid: 16777985
references.citation: Cancer Epidemiol Biomarkers Prev. 2005 Dec;14(12):3015-8
references.pmid: 16365030
references.citation: Genet Test. 1999;3(2):233-6
references.pmid: 10464674
references.citation: Eur J Cancer. 2006 Mar;42(4):528-33
references.pmid: 16359859
references.citation: Breast Cancer Res Treat. 2007 Sep;104(3):299-308
references.pmid: 17063264
references.citation: DNA Cell Biol. 2008 Mar;27(3):127-32
references.pmid: 17979520
references.citation: Blood. 2001 May 15;97(10):3205-9
references.pmid: 11342450
references.citation: Scand J Gastroenterol. 2011 Apr;46(4):436-45
references.pmid: 21128871
references.citation: Asian Pac J Cancer Prev. 2011;12(7):1861-6
references.pmid: 22126580
references.citation: Cancer Epidemiol Biomarkers Prev. 2001 Apr;10(4):397-401
references.pmid: 11319182
references.citation: Cancer Lett. 2004 Aug 10;211(2):199-207
references.pmid: 15219943
references.citation: Breast Cancer Res. 2002;4(6):R14
references.pmid: 12473175
references.citation: World J Gastroenterol. 2006 Dec 21;12(47):7591-7
references.pmid: 17171786
references.citation: Leuk Lymphoma. 2006 Oct;47(10):2070-5
references.pmid: 17071478
references.citation: Clin Cancer Res. 2003 Feb;9(2):743-8
references.pmid: 12576444
references.citation: Cancer Lett. 2009 Jan 8;273(1):55-61
references.pmid: 18789576
references.citation: Am J Hematol. 2007 Sep;82(9):798-801
references.pmid: 17546637
references.citation: J Cancer Res Clin Oncol. 2004 Oct;130(10):574-80
references.pmid: 15449187
references.citation: Nutr Cancer. 2010;62(6):743-9
references.pmid: 20661822
references.citation: Anticancer Res. 2006 Nov-Dec;26(6B):4229-33
references.pmid: 17201138
references.citation: Cancer Lett. 2005 May 10;222(1):57-65
references.pmid: 15837541
references.citation: BMC Cancer. 2010 Oct 04;10:525
references.pmid: 20920350
references.citation: Colorectal Dis. 2012 Sep;14(9):e573-86
references.pmid: 22390411
references.citation: DNA Cell Biol. 2012 Jan;31(1):57-66
references.pmid: 21848426
references.citation: Am J Hum Genet. 1998 May;62(5):1044-51
references.pmid: 9545395
references.citation: Am J Epidemiol. 2008 Mar 1;167(5):505-16
references.pmid: 18162478
references.citation: Cancer Lett. 2002 Jul 8;181(1):65-71
references.pmid: 12430180
references.citation: Ann Hematol. 2007 Dec;86(12):887-95
references.pmid: 17712558
references.citation: Cancer Epidemiol Biomarkers Prev. 2004 Aug;13(8):1331-6
references.pmid: 15298954
references.citation: Carcinogenesis. 2007 Aug;28(8):1718-25
references.pmid: 17468511
references.citation: Gastroenterology. 2006 Oct;131(4):1271-83
references.pmid: 17030196
references.citation: Int J Cancer. 2012 Nov 1;131(9):2103-16
references.pmid: 22307944
references.citation: Cancer Epidemiol Biomarkers Prev. 2009 Apr;18(4):1101-10
references.pmid: 19336565
references.citation: Nat Genet. 1995 May;10(1):111-3
references.pmid: 7647779
references.citation: Arch Gynecol Obstet. 2008 Dec;278(6):517-24
references.pmid: 18351371
references.citation: Circulation. 1998 Dec 8;98(23):2520-6
references.pmid: 9843457
references.citation: Cancer Epidemiol Biomarkers Prev. 2007 Nov;16(11):2416-24
references.pmid: 18006931
references.citation: Anticancer Res. 2004 Sep-Oct;24(5B):3215-9
references.pmid: 15510613
references.citation: Cancer Epidemiol Biomarkers Prev. 2004 Dec;13(12):2175-80
references.pmid: 15598777
references.citation: Cancer Epidemiol Biomarkers Prev. 2003 Nov;12(11 Pt 1):1222-6
references.pmid: 14652285
references.citation: Cancer Biomark. 2009;5(6):233-40
references.pmid: 20037199
references.citation: Eur J Cancer Prev. 2006 Feb;15(1):46-50
references.pmid: 16374229
references.citation: Cancer Causes Control. 2011 Jan;22(1):63-72
references.pmid: 21052817
references.citation: J Natl Cancer Inst. 2006 Nov 15;98(22):1607-22
references.pmid: 17105984
references.citation: Anticancer Res. 2005 May-Jun;25(3B):2249-52
references.pmid: 16158971
references.citation: Scand J Gastroenterol. 2005 Jan;40(1):109-11
references.pmid: 15841723
references.citation: Biomarkers. 2007 Jan-Feb;12(1):61-75
references.pmid: 17438654
references.citation: Cancer Epidemiol Biomarkers Prev. 2004 May;13(5):787-94
references.pmid: 15159311
references.citation: Indian J Cancer. 2010 Jan-Mar;47(1):40-5
references.pmid: 20071789
references.citation: Breast Cancer Res Treat. 2007 Dec;106(2):263-71
references.pmid: 17260091
references.citation: Cancer Epidemiol Biomarkers Prev. 2004 Feb;13(2):285-92
references.pmid: 14973104
references.citation: Cancer Epidemiol Biomarkers Prev. 2005 Jun;14(6):1477-84
references.pmid: 15941959
references.citation: Breast Cancer Res Treat. 2003 Sep;81(2):169-72
references.pmid: 14572159
references.citation: Cancer Sci. 2005 Sep;96(9):535-42
references.pmid: 16128738
references.citation: Gynecol Oncol. 2005 Jan;96(1):173-80
references.pmid: 15589597
references.citation: J Nephrol. 2000 Jan-Feb;13(1):20-33
references.pmid: 10720211
references.citation: Anticancer Res. 2003 Nov-Dec;23(6D):5149-52
references.pmid: 14981981
references.citation: Cancer Sci. 2007 Sep;98(9):1439-46
references.pmid: 17596206
references.citation: Carcinogenesis. 1997 Dec;18(12):2307-11
references.pmid: 9450474
references.citation: Mutat Res. 2011 Mar 18;721(1):74-80
references.pmid: 21211571
references.citation: Biomarkers. 2007 Nov-Dec;12(6):635-44
references.pmid: 17972183
references.citation: J Laryngol Otol. 2005 May;119(5):371-6
references.pmid: 15949101
references.citation: J Epidemiol. 2010;20(4):329-38
references.pmid: 20551579
references.citation: Curr Drug Metab. 2005 Feb;6(1):37-46
references.pmid: 15720206
references.citation: J Cancer Res Clin Oncol. 2006 Apr;132(4):219-22
references.pmid: 16365753