Cancer Causes & Control

, Volume 19, Issue 7, pp 751–758

Folate and MTHFR: risk of adenoma recurrence in the Polyp Prevention Trial

  • Gwen Murphy
  • Leah B. Sansbury
  • Amanda J. Cross
  • Rachael Stolzenberg-Solomon
  • Adeyinka Laiyemo
  • Paul S. Albert
  • Zhuoqiao Wang
  • Arthur Schatzkin
  • Teresa Lehman
  • Aravind Kalidindi
  • Rama Modali
  • Elaine Lanza
Original Paper

Abstract

Background

Low dietary folate intake has been associated with colorectal cancer risk and adenoma recurrence. A C/T transition at position 677 in the gene encoding methlylenetetrahydrofolate reductase (MTHFR C677T) has been reported to interact with folate intake to modulate colorectal adenoma recurrence or cancer risk.

Methods

We investigated the association between MTHFR, total folate, and the risk of colorectal adenoma recurrence in the Polyp Prevention Trial. We compared 625 individuals with any adenoma recurrence after 4 years (266 individuals with multiple (≥2) recurrent adenomas and 101 individuals with advanced adenoma recurrence) to 978 individuals with no adenoma recurrence. Odds ratios (OR) and 95% confidence intervals (CI) for risk of adenoma recurrence were calculated using unconditional logistic regression. We also investigated effect modification of the MTHFR genotype associations by total folate intake.

Results

In general, no statistically significant associations were found between quartile of folate intake (dietary or total) and adenoma recurrence. The MTHFR CT genotype was associated with a significantly increased risk of multiple adenoma recurrence (OR: 1.34, 95% CI: 1.00, 1.81). No significant interaction was noted for total folate and MTHFR genotype, though an increased risk of recurrence noted for the MTHFR CT genotype was statistically significant only for those individuals with below median intake of total folate.

Conclusion

We report that the MTHFR 677 CT genotype was associated with increased risk of adenoma recurrence (specifically multiple adenoma recurrence) 4 years after polypectomy.

Keywords

Folate Methlylenetetrahydrofolate reductase Adenoma 

Abbreviations

CI

Confidence interval

CRC

Colorectal cancer

DFE

Dietary folate equivalents

FFQ

Food frequency questionnaire

MTHFR

Methylenetetrahydrofolate reductase

OR

Odds ratio

PPT

Polyp prevention trial

RR

Relative risk

SNP

Single nucleotide polymorphism

References

  1. 1.
    World Cancer Research Fund/American Institute for Cancer Research (1997) Food, nutrition and the prevention of cancer: a global perspective. Washington, DC: American Institute for Cancer ResearchGoogle Scholar
  2. 2.
    Potter JD, Slattery ML, Bostick RM, Gapstur SM (1993) Colon cancer: a review of the epidemiology. Epidemiol Rev 15:499–545PubMedGoogle Scholar
  3. 3.
    Slattery ML, Boucher KM, Caan BJ, Potter JD, Ma KN (1998) Eating patterns and risk of colon cancer. Am J Epidemiol 148:4–16 Jul 1PubMedGoogle Scholar
  4. 4.
    World Cancer Research Fund/American Institute for Cancer Research. (2007) Food, nutrition, physical activity and the prevention of cancer: a global perspective. Washington DC AICRGoogle Scholar
  5. 5.
    Yetley EA, Rader JI (2004) Modeling the level of fortification and post-fortification assessments: U.S. experience. Nutr Rev 62:S50–S59; discussion S60–1 JunPubMedCrossRefGoogle Scholar
  6. 6.
    Powers HJ (2005) Interaction among folate, riboflavin, genotype, and cancer, with reference to colorectal and cervical cancer. J Nutr 135:2960S–2966S DecPubMedGoogle Scholar
  7. 7.
    Freudenheim JL, Graham S, Marshall JR et al (1991) Folate intake and carcinogenesis of the colon and rectum. Int J Epidemiol 20:368–374 JunPubMedCrossRefGoogle Scholar
  8. 8.
    Kim YI (2007) Folate and colorectal cancer: An evidence-based critical review. Mol Nutr Food Res 51:267–292 MarPubMedCrossRefGoogle Scholar
  9. 9.
    Martinez ME, Giovannucci E, Jiang R et al (2006) Folate fortification, plasma folate, homocysteine and colorectal adenoma recurrence. Int J Cancer 119:1440–1446 Sep 15PubMedCrossRefGoogle Scholar
  10. 10.
    Choi SW, Mason JB (2002) Folate status: effects on pathways of colorectal carcinogenesis. J Nutr 132:2413S–2418S AugPubMedGoogle Scholar
  11. 11.
    Sanjoaquin MA, Allen N, Couto E, Roddam AW, Key TJ (2005) Folate intake and colorectal cancer risk: a meta-analytical approach. Int J Cancer 113:825–828 Feb 20PubMedCrossRefGoogle Scholar
  12. 12.
    Van Guelpen B, Hultdin J, Johansson I et al (2006) Low folate levels may protect against colorectal cancer. Gut 55:1461–1466 OctPubMedCrossRefGoogle Scholar
  13. 13.
    Cole BF, Baron JA, Sandler RS et al (2007) Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. Jama 297:2351–2359 Jun 6PubMedCrossRefGoogle Scholar
  14. 14.
    Kim YI (2004) Folate, colorectal carcinogenesis, and DNA methylation: lessons from animal studies. Environ Mol Mutagen 44:10–25PubMedCrossRefGoogle Scholar
  15. 15.
    Hoffman RM (1984) Altered methionine metabolism, DNA methylation and oncogene expression in carcinogenesis. A review and synthesis. Biochim Biophys Acta 738:49–87PubMedGoogle Scholar
  16. 16.
    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 10:111–113 MayPubMedCrossRefGoogle Scholar
  17. 17.
    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 62:1044–1051 MayPubMedCrossRefGoogle Scholar
  18. 18.
    Kono S, Chen K (2005) Genetic polymorphisms of methylenetetrahydrofolate reductase and colorectal cancer and adenoma. Cancer Sci 96:535–542 SepPubMedCrossRefGoogle Scholar
  19. 19.
    Giovannucci E, Chen J, Smith-Warner SA et al (2003) Methylenetetrahydrofolate reductase, alcohol dehydrogenase, diet, and risk of colorectal adenomas. Cancer Epidemiol Biomarkers Prev 12:970–979 OctPubMedGoogle Scholar
  20. 20.
    Hirose M, Kono S, Tabata S et al (2005) Genetic polymorphisms of methylenetetrahydrofolate reductase and aldehyde dehydrogenase 2, alcohol use and risk of colorectal adenomas: self-defense forces health study. Cancer Sci 96:513–518 AugPubMedCrossRefGoogle Scholar
  21. 21.
    Marugame T, Tsuji E, Inoue H et al (2000) Methylenetetrahydrofolate reductase polymorphism and risk of colorectal adenomas. Cancer Lett 151:181–186 Apr 14PubMedCrossRefGoogle Scholar
  22. 22.
    Ulrich CM, Kampman E, Bigler J et al (1999) Colorectal adenomas and the C677T MTHFR polymorphism: evidence for gene-environment interaction? Cancer Epidemiol Biomarkers Prev 8:659–668 AugPubMedGoogle Scholar
  23. 23.
    Levine AJ, Siegmund KD, Ervin CM et al (2000) The methylenetetrahydrofolate reductase 677C–>T polymorphism and distal colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev 9:657–663 JulPubMedGoogle Scholar
  24. 24.
    Schatzkin A, Lanza E, Corle D et al (2000) Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas. Polyp prevention trial study group. N Engl J Med 342:1149–1155 Apr 20PubMedCrossRefGoogle Scholar
  25. 25.
    Block G, Hartman AM, Dresser CM et al (1986) A data-based approach to diet questionnaire design and testing. Am J Epidemiol 124:453–469 SepPubMedGoogle Scholar
  26. 26.
    Mares-Perlman JA, Klein BE, Klein R et al (1993) A diet history questionnaire ranks nutrient intakes in middle-aged and older men and women similarly to multiple food records. J Nutr 123:489–501 MarPubMedGoogle Scholar
  27. 27.
    Flood A, Caprario L, Chaterjee N et al (2002) Folate, methionine, alcohol, and colorectal cancer in a prospective study of women in the United States. Cancer Causes Control 13:551–561 AugPubMedCrossRefGoogle Scholar
  28. 28.
    Sansbury LB, Bergen AW, Wanke KL et al (2006) Inflammatory cytokine gene polymorphisms, nonsteroidal anti-inflammatory drug use, and risk of adenoma polyp recurrence in the polyp prevention trial. Cancer Epidemiol Biomarkers Prev 15:494–501 MarPubMedCrossRefGoogle Scholar
  29. 29.
    Kokoris M, Dix K, Moynihan K et al (2000) High-throughput SNP genotyping with the Masscode system. Mol Diagn 5:329–340 DecPubMedCrossRefGoogle Scholar
  30. 30.
    Martinez ME, Thompson P, Jacobs ET et al (2006) Dietary factors and biomarkers involved in the methylenetetrahydrofolate reductase genotype-colorectal adenoma pathway. Gastroenterology 131:1706–1716 DecPubMedCrossRefGoogle Scholar
  31. 31.
    van den Donk M, Buijsse B, van den Berg SW et al (2005) Dietary intake of folate and riboflavin, MTHFR C677T genotype, and colorectal adenoma risk: a Dutch case–control study. Cancer Epidemiol Biomarkers Prev 14:1562–1566 JunPubMedCrossRefGoogle Scholar
  32. 32.
    Hubner RA, Muir KR, Liu J-F et al (2006) Folate metabolism polymorphisms influence risk of colorectal adenoma recurrence. Cancer Epidemiol Biomarkers Prev 15:1607–1613 September 1, 2006PubMedCrossRefGoogle Scholar
  33. 33.
    Ryan BM, Molloy AM, McManus R et al (2001) The methylenetetrahydrofolate reductase (MTHFR) gene in colorectal cancer: role in tumor development and significance of allelic loss in tumor progression. Int J Gastrointest Cancer 30:105–111PubMedCrossRefGoogle Scholar
  34. 34.
    Slattery ML, Potter JD, Samowitz W, Schaffer D, Leppert M (1999) Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev 8:513–518 JunPubMedGoogle Scholar
  35. 35.
    Winawer SJ, Zauber AG, Fletcher RH et al (2006) Guidelines for Colonoscopy Surveillance after Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society. CA Cancer J Clin 56:143–159 May 1, 2006PubMedCrossRefGoogle Scholar
  36. 36.
    Bonithon-Kopp C, Piard F, Fenger C et al (2004) Colorectal adenoma characteristics as predictors of recurrence. Dis Colon Rectum 47:323–333 MarPubMedCrossRefGoogle Scholar
  37. 37.
    Robertson DJ, Greenberg ER, Beach M et al (2005) Colorectal cancer in patients under close colonoscopic surveillance. Gastroenterology 129:34–41 JulPubMedCrossRefGoogle Scholar
  38. 38.
    Winawer SJ, Zauber AG, O’Brien MJ et al (1993) Randomized comparison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous polyps. The National Polyp Study Workgroup. N Engl J Med 328:901–906 Apr 1PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Gwen Murphy
    • 1
    • 2
    • 3
  • Leah B. Sansbury
    • 1
    • 2
  • Amanda J. Cross
    • 4
  • Rachael Stolzenberg-Solomon
    • 4
  • Adeyinka Laiyemo
    • 1
    • 2
  • Paul S. Albert
    • 5
  • Zhuoqiao Wang
    • 6
  • Arthur Schatzkin
    • 4
  • Teresa Lehman
    • 7
  • Aravind Kalidindi
    • 7
  • Rama Modali
    • 7
  • Elaine Lanza
    • 2
  1. 1.Cancer Prevention Fellowship ProgramOffice of Preventive OncologyBethesdaUSA
  2. 2.Center for Cancer ResearchNational Cancer InstituteBethesdaUSA
  3. 3.Infection & Immunoepidemiology Branch, Division of Cancer Epidemiology and GeneticsNational Cancer InstituteRockvilleUSA
  4. 4.Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaUSA
  5. 5.Biometric Research Branch, Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaUSA
  6. 6.Information Management Services, Inc.RockvilleUSA
  7. 7.Bioserve Biotechnologies, Ltd.LaurelUSA

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