Background A number of studies have explored the association between methyl enetetrahydrofolate reductase (MTHFR) C677T polymorphism and susceptibility to cervical cancer and cervical intraepithelial neoplasia (CIN). However, results remained controversial. To address this gap, we decided to conduct a meta-analysis of all available published studies. Methods Electronic literature searches of the PubMed, EmBase and Medline databases were performed up to April 30, 2012. Fixed-effects or random-effects model was used to calculate the pooled ORs for different genetic models. Results A total of 12 case-control studies were ultimately identified. No statistical correlation was found between C677T variants and cervical cancer for the overall population. However, subgroup analyses on the White women pointed to a significant protective effect for individuals heterozygous or homozygous for the T-allele (for CT vs. CC: OR = 0.72, 95% CI 0.59–0.88; for TT vs. CC: OR = 0.69, 95% CI = 0.49–0.97; for CT+TT vs. CC: OR = 0.71, 95% CI 0.59–0.86). C677T variants were associated with neither combined nor stratified CIN among the overall population. Conclusions This meta-analysis suggests that White women with mutant C677T genotypes might have a lower risk of cervical cancer, yet lacking enough statistical robustness. Further investigations are needed to get more insight into the role of this polymorphism in cervical carcinogenesis.
References
[1]
Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55: 74–108.
[2]
Parkin DM, Bray F (2006) Chapter 2: The burden of HPV-related cancers. Vaccine 24: 11–25.
[3]
Sadeghi SB, Sadeghi A, Robboy SJ (1988) Prevalence of dysplasia and cancer of the cervix in a nationwide planned parenthood population. Cancer 61: 2359–2361.
[4]
Luthra UK, Prabhakar AK, Seth P, Agarwal SS, Murthy NS, et al. (1987) Natural history of precancerous and early cancerous lesions of the uterine cervix. Acta Cytol 31: 226–234.
[5]
Shin HR, Park S, Hwang SY, Kim JE, Jung KW, et al. (2008) Trends in cervical cancer mortality in Korea 1993–2002: corrected mortality using National death certification data and national cancer incidence data. Int J Cancer 122: 393–397.
[6]
American Cancer Society (2011) Cancer facts & figures 2011. Chapter 2, Selected Cancers: Uterine Cervix. pp. 22–23.
[7]
Schiffman MH, Bauer HM, Hoover RN, Glass AG, Cadell DM, et al. (1993) Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst 85: 958–964.
[8]
Cerqueira EM, Santoro CL, Donozo NF, Freitas BA, Pereira CA, et al. (1998) Genetic damage in exfoliated cells of the uterine cervix. Association and interaction between cigarette smoking and progression to malignant transformation? Acta Cytol 42: 639–649.
[9]
Romney SL, Basu J, Vermund S, Palan PR, Duttagupta C (1987) Plasma reduced and total ascorbic acid in human uterine cervix dysplasia and cancer. Ann N Y Acad Sci 498: 132–143.
[10]
Goodman MT, McDuffie K, Hernandez B, Wilkens LR, Selhub J (2000) Case-control study of plasma folate, homocysteine, vitamin B(12), and cysteine as markers of cervical dysplasia. Cancer 89: 376–382.
[11]
VanEenwyk J, Davis FG, Colman N (1992) Folate, vitamin C, and cervical intraepithelial neoplasia. Cancer Epidemiol Biomarkers Prev 1: 119–124.
[12]
Piyathilake CJ, Macaluso M, Brill I, Heimburger DC, Partridge EE (2007) Lower red blood cell folate enhances the HPV-16-associated risk of cervical intraepithelial neoplasia. Nutrition 23: 203–210.
[13]
Piyathilake CJ, Macaluso M, Alvarez RD, Bell WC, Heimburger DC, et al. (2009) Lower risk of cervical intraepithelial neoplasia in women with high plasma folate and sufficient vitamin B12 in the post-folic acid fortification era. Cancer Prev Res (Phila) 2: 658–664.
[14]
Flatley JE, McNeir K, Balasubramani L, Tidy J, Stuart EL, et al. (2009) Folate status and aberrant DNA methylation are associated with HPV infection and cervical pathogenesis. Cancer Epidemiol Biomarkers Prev 18: 2782–2789.
[15]
Piyathilake CJ, Macaluso M, Johanning GL, Whiteside M, Heimburger DC, et al. (2000) Methylenetetrahydrofolate reductase (MTHFR) polymorphism increases the risk of cervical intraepithelial neoplasia. Anticancer Res 20: 1751–1757.
[16]
Goodman MT, McDuffie K, Hernandez B, Wilkens LR, Bertram CC, et al. (2001) Association of methylenetetrahydrofolate reductase polymorphism C677T and dietary folate with the risk of cervical dysplasia. Cancer Epidemiol Biomarkers Prev 10: 1275–1280.
[17]
Lambropoulos AF, Agorastos T, Foka ZJ, Chrisafi S, Constantinidis TC, et al. (2003) Methylenetetrahydrofolate reductase polymorphism C677T is not associated to the risk of cervical dysplasia. Cancer Lett 191: 187–191.
[18]
Sull JW, Jee SH, Yi S, Lee JE, Park JS, et al. (2004) The effect of methylenetetrahydrofolate reductase polymorphism C677T on cervical cancer in Korean women. Gynecol Oncol 95: 557–563.
[19]
Kang S, Kim JW, Kang GH, Park NH, Song YS, et al. (2005) Polymorphism in folate- and methionine-metabolizing enzyme and aberrant CpG island hypermethylation in uterine cervical cancer. Gynecol Oncol 96: 173–280.
[20]
Zoodsma M, Nolte IM, Schipper M, Oosterom E, van der Steege G, et al. (2005) Methylenetetrahydrofolate reductase (MTHFR) and susceptibility for (pre)neoplastic cervical disease. Hum Genet 116: 247–254.
[21]
Delgado-Enciso I, Martínez-Garza SG, Rojas-Martínez A, Espinoza-Gomez F, Canseco-Avila LM, et al. (2006) The effect of MTHFR polymorphisms, pregnancy and first intercourse on cervical cancer in a population from the Northeastern Mexico. Rev Invest Clin 58: 462–469.
[22]
Shekari M, Sobti RC, Kordi Tamandani DM, Suri V (2008) Impact of methylenetetrahydrofolate reductase (MTHFR) codon (677) and methionine synthase (MS) codon (2756) on risk of cervical carcinogenesis in North Indian population. Arch Gynecol Obstet 278: 517–524.
[23]
Kohaar I, Kumar J, Thakur N, Hussain S, Niyaz MK, et al. (2010) Homocysteine levels are associated with cervical cancer independent of methylene tetrahydrofolate reductase gene (MTHFR) polymorphisms in Indian population. Biomarkers 15: 61–68.
[24]
Mostowska A, Myka M, Lianeri M, Roszak A, Jagodzinski PP (2011) Folate and choline metabolism gene variants and development of uterine cervical carcinoma. Clin Biochem 44: 596–600.
[25]
Prasad VV, Wilkhoo H (2011) Association of the functional polymorphism C677T in the methylenetetrahydrofolate reductase gene with colorectal, thyroid, breast, ovarian, and cervical cancers. Onkologie 34: 422–426.
[26]
Tong SY, Kim MK, Lee JK, Lee JM, Choi SW, et al. (2011) Common polymorphisms in methylenetetrahydrofolate reductase gene are associated with risks of cervical intraepithelial neoplasia and cervical cancer in women with low serum folate and vitamin B12. Cancer Causes Control 22: 63–72.
[27]
Salanti G, Amountza G, Ntzani EE, Ioannidis JP (2005) Hardy-Weinberg equilibrium in genetic association studies: an empirical evaluation of reporting, deviations, and power. Eur J Hum Genet 13: 840–848.
[28]
Office of Management and Budget (2003) Revisions to the Standards for the Classification of Federal Data on Race and Ethnicity. Avaliable on http://www.whitehouse.gov/omb/fedreg_199？7standards/
[29]
Cochran WG (1954) The combination of estimates from different experiments. Biometrics 10: 101–129.
[30]
Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22: 719–748.
[31]
DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7: 177–188.
[32]
Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test of publication bias. Biometrics 50: 1088–1101.
[33]
Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315: 629–634.
[34]
Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, et al. (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10: 111–113.
[35]
Molloy AM, Daly S, Mills JL, Kirke PN, Whitehead AS, et al. (1997) Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. Lancet 349: 1591–1593.
[36]
Duthie SJ, Narayanan S, Brand GM, Pirie L, Grant G (2002) Impact of folate deficiency on DNA stability. J Nutr 132: 2444S–2449S.
[37]
Sheng X, Zhang Y, Zhao E, Lu S, Zheng X, et al. (2012) MTHFR C677T polymorphism contributes to colorectal cancer susceptibility: evidence from 61 case-control studies. Mol Biol Rep [Epub ahead of print] PMID 22729883.
[38]
Yan J, Yin M, Dreyer ZE, Scheurer ME, Kamdar K, et al. (2012) A meta-analysis of MTHFR C677T and A1298C polymorphisms and risk of acute lymphoblastic leukemia in children. Pediatr Blood Cancer 58: 513–518.
[39]
Zacho J, Yazdanyar S, Bojesen SE, Tybj？rg-Hansen A, Nordestgaard BG (2011) Hyperhomocysteinemia, methylenetetrahydrofolate reductase c.677C>T polymorphism and risk of cancer: cross-sectional and prospective studies and meta-analyses of 75,000 cases and 93,000 controls. Int J Cancer 128: 644–652.
[40]
Qi X, Ma X, Yang X, Fan L, Zhang Y, et al. (2010) Methylenetetrahydrofolate reductase polymorphisms and breast cancer risk: a meta-analysis from 41 studies with 16,480 cases and 22,388 controls. Breast Cancer Res Treat 123: 499–506.
[41]
Zhang Y, Chen GQ, Ji Y, Huang B, Shen WS, et al. (2012) Quantitative assessment of the effect of MTHFR polymorphisms on the risk of lung carcinoma. Mol Biol Rep 39: 6203–6211.
[42]
Boccia S, Boffetta P, Brennan P, Ricciardi G, Gianfagna F, et al. (2009) Meta-analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and risk of head and neck and lung cancer. Cancer Lett 273: 55–61.
[43]
Collin SM, Metcalfe C, Zuccolo L, Lewis SJ, Chen L, et al. (2009) 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 18: 2528–39.
[44]
Shaw GM, Lammer EJ, Zhu H, Baker MW, Neri E, et al. (2002) Maternal periconceptional vitamin use, genetic variation of infant reduced folate carrier (A80G), and risk of spina bifida. Am J Med Genet 108: 1–6.
[45]
Colhoun HM, McKeigue PM, Davey Smith G (2003) Problems of reporting genetic associations with complex outcomes. Lancet 361: 865–872.
[46]
van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, et al. (1998) A second common mutation in the methylenetetrahydrofolate reductase gene: An additional risk factor for neural-tube defects? Am J Hum Genet 62: 1044–1051.
[47]
Brinton LA (1992) Epidemiology of cervical cancer-overview. In Munoz N, Bosch FX, Shah KV, Meheus A, editors. The epidemiology of cervical cancer and human papillomavirus. IARC Press, Lyon, France. pp. 3–23.
[48]
Herrero R, Brinton LA, Reeves WC, Brenes MM, Tenorio F, et al. (1990) Sexual behavior, venereal diseases, hygiene practices, and invasive cervical cancer in a high-risk population. Cancer 65: 380–386.
[49]
Schiffman MH, Brinton LA (1995) The epidemiology of cervical carcinogenesis. Cancer 76: 1888–1901.
