Cancer Causes & Control

, Volume 22, Issue 1, pp 63–72 | Cite as

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

  • Seo-yun Tong
  • Mi Kyung Kim
  • Jae Kwan Lee
  • Jong Min Lee
  • Sang Woon Choi
  • Simonetta Friso
  • Eun-Seop Song
  • Kwang Beom Lee
  • Jung Pil Lee
Original paper



We evaluated associations between folate, vitamin B12, and the methylenetetrahydrofolate reductase (MTHFR) gene, and risk of cervical intraepithelial neoplasia (CIN) and cervical cancer.


This multicenter case–control study enrolled 927 Korean women (440 controls, 165 patients with CIN 1, 167 patients with CIN 2/3, and 155 patients with cervical cancer, aged 20–75 years).


Patients with cervical cancer had significantly lower median serum folate and vitamin B12 concentrations vs. controls. Higher serum folate was significantly associated with lower cervical cancer risk (p for linear trend = 0.0058) with a trend for a lower CIN risk after multivariate adjustment. Low folate and the MTHFR 677 C > T variant were associated with a higher risk for CIN2/3 and cervical cancer vs. wild-type or heterozygous genotypes with high folate [OR, 2.39 (1.18–4.85) and 3.19 (1.43–7.13)]. Low vitamin B12 and the MTHFR 677 C > T variant also were associated with a higher risk for CIN 2/3 and cervical cancers [OR, 2.52 (1.17–5.42) and 2.40 (1–5.73)] vs. wild-type or heterozygous status with high vitamin levels.


Serum folate concentration is inversely associated with the risk of cervical cancer, and the MTHFR variant genotype may increase CIN and cervical cancer risk in women with low folate or vitamin B12 status.


Folate Vitamin B12 Genetic polymorphisms Methylenetetrahydrofolate reductase Cervical intraepithelial neoplasia Cervical cancer 



This work was supported in part by a Korea Science and Engineering Foundation (KOSEF) grant funded by the Korean government (MOST) (R01-2006-000-10621-0). The authors’ contributions to this work were as follows: KMK designed the study and obtained funding; ST and SHS drafted the manuscript; KMK, SWC, and SF contributed to the interpretation of the results and manuscript preparation; and JML, JKL, ESS, KBL, and JPL recruited subjects and collected the data. All authors approved the final manuscript. None of the authors report any conflict of interest.


  1. 1.
    Parkin DM, Bray FI, Devesa SS (2001) Cancer burden in the year 2000. The global picture. Eur J Cancer 37(8):S4–66Google Scholar
  2. 2.
    Shin HR, Park S, Hwang SY 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(2):393–397CrossRefPubMedGoogle Scholar
  3. 3.
    Walboomers JMM, Jacobs MV, Manos MM et al (1999) Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189(1):12–19CrossRefPubMedGoogle Scholar
  4. 4.
    Kjellberg L, Hallmans G, Ahren AM et al (2000) Smoking, diet, pregnancy and oral contraceptive use as risk factors for cervical intra-epithelial neoplasia in relation to human papillomavirus infection. Br J Cancer 82(7):1332–1338CrossRefPubMedGoogle Scholar
  5. 5.
    Josefsson AM, Magnusson PK, Ylitalo N et al (2000) Viral load of human papilloma virus 16 as a determinant for development of cervical carcinoma in situ: a nested case-control study. Lancet 355(9222):2189–2193CrossRefPubMedGoogle Scholar
  6. 6.
    Powers HJ (2005) Interaction among folate, riboflavin, genotype, and cancer, with reference to colorectal and cervical cancer. J Nutr 135(12 Suppl):2960S–2966SPubMedGoogle Scholar
  7. 7.
    Piyathilake CJ, Henao OL, Macaluso M et al (2004) Folate is associated with the natural history of high-risk human papillomaviruses. Cancer Res 64(23):8788–8793CrossRefPubMedGoogle Scholar
  8. 8.
    Hernandez BY, McDuffie K, Wilkens LR, Kamemoto L, Goodman MT (2003) Diet and premalignant lesions of the cervix: evidence of a protective role for folate, riboflavin, thiamin, and vitamin B12. Cancer Causes Control 14(9):859–870CrossRefPubMedGoogle Scholar
  9. 9.
    Goodman MT, McDuffie K, Hernandez B et al (2001) Association of methylenetetrahydrofolate reductase polymorphism C677T and dietary folate with the risk of cervical dysplasia. Cancer Epidemiol Biomark Prev 10(12):1275–1280Google Scholar
  10. 10.
    Butterworth CE Jr, Hatch KD, Macaluso M et al (1992) Folate deficiency and cervical dysplasia. Jama 267(4):528–533CrossRefPubMedGoogle Scholar
  11. 11.
    Flatley JE, McNeir K, Balasubramani L et al (2009) Folate status and aberrant DNA methylation are associated with HPV infection and cervical pathogenesis. Cancer Epidemiol Biomark Prev 18(10):2782–2789CrossRefGoogle Scholar
  12. 12.
    Shikany JM, Heimburger DC, Piyathilake CJ, Desmond RA, Greene PG (2004) Effect of folic acid fortification of foods on folate intake in female smokers with cervical dysplasia. Nutrition 20(5):409–414CrossRefPubMedGoogle Scholar
  13. 13.
    Duhr A, Galan P, Hercberg S (1991) Folate status and the immune system. Prog Food Nutr Sci 15:43–60Google Scholar
  14. 14.
    Sedjo RL, Fowler BM, Schneider A, Henning SM, Hatch K, Giuliano AR (2003) Folate, vitamin B12, and homocysteine status. Findings of no relation between human papillomavirus persistence and cervical dysplasia. Nutrition 19(6):497–502CrossRefPubMedGoogle Scholar
  15. 15.
    Shannon J, Thomas DB, Ray RM et al (2002) Dietary risk factors for invasive and in situ cervical carcinomas in Bangkok, Thailand. Cancer Causes Control 13(8):691–699CrossRefPubMedGoogle Scholar
  16. 16.
    Alberg AJ, Selhub J, Shah KV, Viscidi RP, Comstock GW, Helzlsouer KJ (2000) The risk of cervical cancer in relation to serum concentrations of folate, vitamin B12, and homocysteine. Cancer Epidemiol Biomark Prev 9(7):761–764Google Scholar
  17. 17.
    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(2):376–382CrossRefPubMedGoogle Scholar
  18. 18.
    Bailey LB, Gregory JF III (1999) Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risks and impact on folate requirement. J Nutr 129(5):919–922PubMedGoogle Scholar
  19. 19.
    Kang SS, Zhou J, Wong PW, Kowalisyn J, Strokosch G (1988) Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet 43:414–421PubMedGoogle Scholar
  20. 20.
    Jones PA, Laird PW (1999) Cancer epigenetics comes of age. Nat Genet 21:163–167CrossRefPubMedGoogle Scholar
  21. 21.
    Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3(6):415–428PubMedGoogle Scholar
  22. 22.
    Frosst P, Blom HJ, Milos R et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10(1):111–113CrossRefPubMedGoogle Scholar
  23. 23.
    Goyette P, Sumner JS, Milos R et al (1994) Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet 7(2):195–200CrossRefPubMedGoogle Scholar
  24. 24.
    van der Put NM, Gabreels F, Stevens EM et al (1998) A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 62:1044–1051CrossRefPubMedGoogle Scholar
  25. 25.
    Slattery ML, Potter JD, Samowitz W, Schaffer D, Leppert M (1999) Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. Cancer Epidemiol Biomark Prev 8(6):513–518Google Scholar
  26. 26.
    Toffoli G, Gafa R, Russo A et al (2003) Methylenetetrahydrofolate reductase 677 C->T polymorphism and risk of proximal colon cancer in north Italy. Clin Cancer Res 9(2):743–748PubMedGoogle Scholar
  27. 27.
    Ma J, Stampfer MJ, Giovannucci E et al (1997) Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res 57(6):1098–1102PubMedGoogle Scholar
  28. 28.
    Levine AJ, Figueiredo JC, Lee W et al (2010) Genetic variability in the MTHFR gene and colorectal cancer risk using the colorectal cancer family registry. Cancer Epidemiol Biomark Prev 19(1):89–100CrossRefGoogle Scholar
  29. 29.
    Piyathilake CJ, Macaluso M, Johanning GL, Whiteside M, Heimburger DC, Giuliano A (2000) Methylenetetrahydrofolate reductase (MTHFR) polymorphism increases the risk of cervical intraepithelial neoplasia. Anticancer Res 20:1751–1757PubMedGoogle Scholar
  30. 30.
    Rao GG, Kurien A, Gossett D, Griffith WF, Coleman RL, Muller CY (2006) A case-control study of methylenetetrahydrofolate reductase polymorphisms in cervical carcinogenesis. Gynecol Oncol 101(2):250–254CrossRefPubMedGoogle Scholar
  31. 31.
    Zoodsma M, Nolte IM, Schipper M et al (2005) Methylenetetrahydrofolate reductase (MTHFR) and susceptibility for (pre)neoplastic cervical disease. Hum Genet 116(4):247–254CrossRefPubMedGoogle Scholar
  32. 32.
    Sull JW, Jee SH, Yi S et al (2004) The effect of methylenetetrahydrofolate reductase polymorphism C677T on cervical cancer in Korean women. Gynecol Oncol 95(3):557–563CrossRefPubMedGoogle Scholar
  33. 33.
    Lambropoulos AF, Agorastos T, Foka ZJ et al (2003) Methylenetetrahydrofolate reductase polymorphism C677T is not associated to the risk of cervical dysplasia. Cancer Lett 191(2):187–191CrossRefPubMedGoogle Scholar
  34. 34.
    Henao OL, Piyathilake CJ, Waterbort JW et al (2005) Women with polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) are less likely to have cervical intraepithelial neoplasia (CIN) 2 or 3. Int J Cancer 113:991–997CrossRefPubMedGoogle Scholar
  35. 35.
    Wright TC Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ, for the A-SCC (2002) 2001 consensus guidelines for the management of women with cervical cytological abnormalities. JAMA 287(16):2120–2129CrossRefPubMedGoogle Scholar
  36. 36.
    Kim YO, Kim MK, Lee S-A, Yoon YM, Sasaki S (2009) A study testing the usefulness of a dish-based food-frequency questionnaire developed for epidemiological studies in Korea. Br J Nutr 101(8):1218–1227CrossRefPubMedGoogle Scholar
  37. 37.
    Cody RP, Smith JK (1997) Multiple-regression analysis. Applied statistics and the SAS programming language, 4th edn. Upper Saddle River, NJ, Prentice Hall, pp 235–247Google Scholar
  38. 38.
    Hosmer DW, Lemeshow S (2000) Applied logistic regression. John Wiley and Sons, NYCrossRefGoogle Scholar
  39. 39.
    Kim HJ, Kim MK, Kim JU, Ha HY, Choi BY (2010) Major determinants of serum homocysteine concentrations in a Korean population. J Korean Med Sci 25(4):509–516CrossRefPubMedGoogle Scholar
  40. 40.
    Kim YI (2004) Folate, colorectal carcinogenesis, and DNA methylation: lessons from animal studies. Environ Mol Mutagen 44(1):10–25CrossRefPubMedGoogle Scholar
  41. 41.
    Ulrich CM, Potter JD (2007) Folate and cancer-timing is everything. JAMA 297(21):2408–2409CrossRefPubMedGoogle Scholar
  42. 42.
    Gerhard DS, Nguyen LT, Zhang ZY, Borecki IB, Coleman BI, Rader JS (2003) A relationship between methylenetetrahydrofolate reductase variants and the development of invasive cervical cancer. Gynecol Oncol 90(3):560–565CrossRefPubMedGoogle Scholar
  43. 43.
    von der Porten AE, Gregory JF III, Toth JP, Cerda JJ, Curry SH, Bailey LB (1992) In vivo folate kinetics during chronic supplementation of human subjects with deuterium-labeled folic acid. J Nutr 122(6):1293–1299Google Scholar
  44. 44.
    Hatzis C, Bertsias G, Linardakis M, Scott J, Kafatos A (2006) Dietary and other lifestyle correlates of serum folate concentrations in a healthy adult population in Crete, Greece: a cross-sectional study. Nutr J 5(1):5CrossRefPubMedGoogle Scholar
  45. 45.
    Galloway M, Rushworth L (2003) Red cell or serum folate? Results from the National Pathology Alliance benchmarking review. J Clin Pathol 56:924–926CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Seo-yun Tong
    • 1
  • Mi Kyung Kim
    • 2
  • Jae Kwan Lee
    • 3
  • Jong Min Lee
    • 1
  • Sang Woon Choi
    • 4
  • Simonetta Friso
    • 5
  • Eun-Seop Song
    • 6
  • Kwang Beom Lee
    • 7
  • Jung Pil Lee
    • 8
  1. 1.Department of Obstetrics and GynecologyEast–West Neo Medical Center, Kyunghee University College of MedicineSeoulKorea
  2. 2.Cancer Epidemiology BranchNational Cancer CenterGoyang-siKorea
  3. 3.College of MedicineKorea UniversitySeoulKorea
  4. 4.Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts UniversityBostonUSA
  5. 5.University of Verona School of MedicineVeronaItaly
  6. 6.The Inha UniversityIncheonKorea
  7. 7.Gil Medical CenterGachon University of Medicine and ScienceInchonKorea
  8. 8.Ajou University School of MedicineSuwonKorea

Personalised recommendations