Skip to main content

Advertisement

Springer Nature Link
Log in

Folate Status and Risk of Colorectal Polyps in African Americans

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Dietary folate status appears to influence risk for colorectal cancer possibly by alterations in DNA methylation and nucleotide precursor pools. Polymorphisms (677C→T and 1298A→C) in methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, determines enzyme activity. The frequency of polymorphisms in the gene varies extensively in different populations. We sought to determine the association between folate status, folate metabolism, DNA methylation, tobacco, alcohol consumption, and the risk of colorectal adenomas in African Americans. Among 58 patients who underwent a clinically indicated colonoscopy, 23 patients with histology confirmed colorectal polyps and 35 patients without were recruited for a case-control study. Blood samples were collected from fasting patients for determination of serum and red blood cell (RBC) folate, homocysteine, vitamin B12, and methylation status. Polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) technique was performed to identify the MTHFR 677 C→T polymorphism and specific PCR was used to analyze adenomatous polyposis coli (APC) gene-promoter sequence methylation. Among 23 cases, 49 polyps (adenomatous, n = 41 and hyperplastic, n= 8) were identified. Twenty-eight (57%) of the polyps were on the left side and 21 (42%) were on the right side of the colon. There was no association between the presence of colon polyps and levels of folate (serum, RBC), vitamin B12, or homocysteine. Forty-eight individuals (84%) were homozygous for 677 CC. Of these individuals, 18 (37.5%) had ≥1 colorectal polyps, whereas 30 (62.5%) had no polyps. Nine individuals were heterozygous for 677 CT, and 4 (44%) of these individuals had colon polyps. Eighty-eight percent of the APC gene-promoter sequences tested using peripheral blood DNA from patients were unmethylated. Among the individuals who showed APC methylation, 66% had polyps; 33% were polyp free using their blood DNA. There was highly significant association between smoking and alcohol consumption with the presence of a colon polyp (P= .0006 and P= .05, respectively). In conclusion, the lack of the 677 TT may be a significant risk factor for colon neoplasm in the African-American population. Smoking and alcohol consumption were found to be risk factors for colon polyps. APC gene-promoter sequence methylation found in peripheral blood may be an indicator of risk for polyp formation and an important screening tool.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Jemal A, Thomas A, Murray T, Thun M (2002) Cancer statistics, 2002. CA Cancer J Clin 52:23–47

    Article  PubMed  Google Scholar 

  2. Carethers JM (1999) Racial and ethnic factors in the genetic pathogenesis of colorectal cancer. J Assoc Acad Minor Phys 10:59–67

    PubMed  CAS  Google Scholar 

  3. Ward R, Meagher A, Tomlinson I, O’Connor T, Norrie M, Wu R, Hawkins N (2001) Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut 48:821–829

    Article  PubMed  CAS  Google Scholar 

  4. Boyer JC, Umar A, Risinger JI, Lipford JR, Kane M, Yin S, Barrett JC, Kolodner RD, Kunkel TA (1995) Microsatellite instability, mismatch repair deficiency, and genetic defects in human cancer cell lines. Cancer Res 55:6063–6070

    PubMed  CAS  Google Scholar 

  5. Terry P, Giovannucci E, Michels KB, Bergkvist L, Hansen H, Holmberg L, Wolk A (2001) Fruit, vegetables, dietary fiber, and risk of colorectal cancer. J Natl Cancer Inst 93:525–533

    Article  PubMed  CAS  Google Scholar 

  6. Giovannucci E, Egan KM, Hunter DJ, Stampfer MJ, Colditz GA, Willett WC, Speizer FE (1995) Aspirin and the risk of colorectal cancer in women [see comments]. N Engl J Med 333:609–614

    Article  PubMed  CAS  Google Scholar 

  7. La Vecchia C, Negri E, Pelucchi C, Franceschi S (2002) Dietary folate and colorectal cancer. Int J Cancer 102:545–547

    Article  PubMed  CAS  Google Scholar 

  8. Fuchs CS, Willett WC, Colditz GA, Hunter DJ, Stampfer MJ, Speizer FE, Giovannucci EL (2002) The influence of folate and multivitamin use on the familial risk of colon cancer in women. Cancer Epidemiol Biomarkers Prev 11:227–234

    PubMed  CAS  Google Scholar 

  9. Le Marchand L, Wilkens LR, Kolonel LN, Henderson BE (2005) The MTHFR C677T polymorphism and colorectal cancer: The multiethnic cohort study. Cancer Epidemiol Biomarkers Prev 14:1198–1203

    Article  PubMed  CAS  Google Scholar 

  10. Ma J, Stampfer MJ, Giovannucci E, Artigas C, Hunter DJ, Fuchs C, Willett WC, Selhub J, Hennekens CH, Rozen R (1997) Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res 57:1098–1102

    PubMed  CAS  Google Scholar 

  11. Chen J, Giovannucci E, Kelsey K, Rimm EB, Stampfer MJ, Colditz GA, Spiegelman D, Willett WC, Hunter DJ (1996) A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res 56:4862–4864

    PubMed  CAS  Google Scholar 

  12. Parker SL, Tong T, Bolden S, Wingo PA (1996) Cancer statistics, 1996. CA Cancer J Clin 46:5–27

    PubMed  CAS  Google Scholar 

  13. Samowitz WS, Albertsen H, Herrick J, Levin TR, Sweeney C, Murtaugh MA, Wolff RK, Slattery ML (2005) Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology 129:837–845

    Article  PubMed  CAS  Google Scholar 

  14. Marugame T, Tsuji E, Inoue H, Shinomiya S, Kiyohara C, Onuma K, Hamada H, Koga H, Handa K, Hayabuchi H, Kono S (2000) Methylenetetrahydrofolate reductase polymorphism and risk of colorectal adenomas. Cancer Lett 151:181–186

    Article  PubMed  CAS  Google Scholar 

  15. Ulrich CM, Kampman E, Bigler J, Schwartz SM, Chen C, Bostick R, Fosdick L, Beresford SA, Yasui Y, Potter JD (1999) Colorectal adenomas and the C677T MTHFR polymorphism: Evidence for gene-environment interaction? Cancer Epidemiol Biomarkers Prev 8:659–668

    PubMed  CAS  Google Scholar 

  16. Ulvik A, Vollset S, Hansen S, Gislefoss R, Jellum E, Ueland PM (2004) Colorectal cancer and the methylenetetrahydrofolate reductase 677C→T and methionine synthase 2756A→G polymorphisms: A study of 2,168 case-control pairs from the JANUS cohort. Cancer Epidemiol Biomarkers Prev 13:2175–2180

    PubMed  CAS  Google Scholar 

  17. Konrad C, Muller G, Langer C, Kuhlenbaumer G, Berger K, Nabavi D, Dziewas R, Stogbauer F, Ringelstein E, Unker R (2004) Plasma homocysteine, MTHFR C677T, CBS 844ins68bp, and MTHFD1 G1958A polymorphisms in spontaneous cervical artery dissections. J Neurol 251:1242–1248

    Article  PubMed  CAS  Google Scholar 

  18. Shelnutt K, Kauwell G, Gregory J, Maneval D, Quinlivan E, Theriaque D, Henderson G, Bailey L (2004) Methylenetetrahydrofolate reductase 677C→T polymorphism affects DNA methylation in response to controlled folate intake in young women. J Nutr Biochem 15:554–560

    Article  PubMed  CAS  Google Scholar 

  19. Zhang J, Zotz R, Li Y, Wang R, Kiel S, Schulz W, Wen D, Chen Z, Zhang L, Wang S, Gabbert H, Sarbia MJ (2004) Methylenetetrahydrofolate reductase C677T polymorphism and predisposition towards esophageal squamous cell carcinoma in a German Caucasian and a northern Chinese population. Cancer Res Clin Oncol 130:574–580

    CAS  Google Scholar 

  20. Lin J, Spitz M, Wang Y, Schabath M, Gorlov I, Hernandez L, Pillow P, Grossman H, Wu X (2004) Polymorphisms of folate metabolic genes and susceptibility to bladder cancer: A case-control study. Carcinogenesis 25:1639–1647

    Article  PubMed  CAS  Google Scholar 

  21. Sarrio D, Moreno-Bueno G, Hardisson D, Sanchez-Estevez C, Guo M, Herman JG, Gamallo C, Esteller M, Palacios J (2003) Epigenetic and genetic alterations of APC and CDH1 genes in lobular breast cancer: relationships with abnormal E-cadherin and catenin expression and microsatellite instability. Int J Cancer 106:208–215

    Article  PubMed  CAS  Google Scholar 

  22. Fleisher AS, Esteller M, Wang S, Tamura G, Suzuki H, Yin J, Zou TT, Abraham JM, Kong D, Smolinski KN, Shi YQ, Rhyu MG, Powell SM, James SP, Wilson KT, Herman JG, Meltzer SJ (1999) Hypermethylation of the hMLH1 gene promoter in human gastric cancers with microsatellite instability. Cancer Res 59:1090–1095

    PubMed  CAS  Google Scholar 

  23. Green RA, Kaplan KB (2003) Chromosome instability in colorectal tumor cells is associated with defects in microtubule plus-end attachments caused by a dominant mutation in APC. J Cell Biol 163:949–961

    Article  PubMed  CAS  Google Scholar 

  24. Van Den Brink GR, Bleuming SA, Hardwick JC, Schepman BL, Offerhaus GJ, Keller JJ, Nielsen C, Gaffield W, Van Deventer SJ, Roberts DJ, Peppelenbosch MP (2004) Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiation. Nat Genet 36:277–282

    Article  PubMed  CAS  Google Scholar 

  25. Moreno-Bueno G, Hardisson D, Sanchez C, Sarrio D, Cassia R, Garcia-Rostan G, Prat J, Guo M, Herman JG, Matias-Guiu X, Esteller M, Palacios J (2002) Abnormalities of the APC/beta-catenin pathway in endometrial cancer. Oncogene 21:7981–7990

    Article  PubMed  CAS  Google Scholar 

  26. Tomeo CA, Colditz GA, Willett WC, Giovannucci E, Platz E, Rockhill B, Dart H, Hunter DJ (1999) Harvard Report on Cancer Prevention. Vol. 3: Prevention of colon cancer in the United States. Cancer Causes Control 10:167–180

    Article  PubMed  CAS  Google Scholar 

  27. Wickramasinghe SN, Fida S (1994) Bone marrow cells from vitamin B12- and folate-deficient patients misincorporate uracil into DNA. Blood 83:1656–1661

    PubMed  CAS  Google Scholar 

  28. Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, Morgan G (1999) Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci USA 96:12810–12815

    Article  PubMed  CAS  Google Scholar 

  29. Duthie SJ (1999) Folic acid deficiency and cancer: mechanisms of DNA instability. Br Med Bull 55:578–592

    Article  PubMed  CAS  Google Scholar 

  30. Reidy JA (1987) Folate- and deoxyuridine-sensitive chromatid breakage may result from DNA repair during G2. Mutat Res 192:217–219

    Article  PubMed  CAS  Google Scholar 

  31. Jung B, Doctolero RT, Tajima A, Nguyen AK, Keku T, Sandler RS, Carethers JM (2004) Loss of activin receptor type 2 protein expression in microsatellite unstable colon cancers. Gastroenterology 126:654–659

    Article  PubMed  CAS  Google Scholar 

  32. Rosenberg L, Palmer JR, Zauber AG, Warshauer ME, Stolley PD, Shapiro S (1991) A hypothesis: Nonsteroidal anti-inflammatory drugs reduce the incidence of large-bowel cancer [see comments]. J Natl Cancer Inst 83:355–358

    Article  PubMed  CAS  Google Scholar 

  33. Nagasaka T, Sasamoto H, Notohara K, Cullings HM, Takeda M, Kimura K, Kambara T, MacPhee DG, Young J, Leggett BA, Jass JR, Tanaka N, Matsubara N (2004) Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation. J Clin Oncol 22:4584–4594

    Article  PubMed  CAS  Google Scholar 

  34. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP, et al. (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10:111–113

    Article  PubMed  CAS  Google Scholar 

  35. McAndrew PE, Brandt JT, Pearl DK, Prior TW (1996) The incidence of the gene for thermolabile methylene tetrahydrofolate reductase in African Americans. Thromb Res 83:195–198

    Article  PubMed  CAS  Google Scholar 

  36. Toffoli G, Gafa R, Russo A, Lanza G, Dolcetti R, Sartor F, Libra M, Viel A, Boiocchi M (2003) Methylenetetrahydrofolate reductase 677 C→T polymorphism and risk of proximal colon cancer in north Italy. Clin Cancer Res 9:743–748

    PubMed  CAS  Google Scholar 

  37. Martinez-Balbas MA, Bannister AJ, Martin K, Haus-Seuffert P, Meisterernst M, Kouzarides T (1998) The acetyltransferase activity of CBP stimulates transcription. Embo J 17:2886–2893

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Grant #U54A91431, the National Cancer Institute, NIH, and the Marcia Johnson award from Howard University.

Author information

Authors and Affiliations

  1. Cancer Center and Department of Medicine, Cancer Center and Department of Medicine, Howard University College of Medicine, 2041 Georgia Avenue, N.W., Washington, DC, 20060, USA

    H. Ashktorab, R. Begum, A. Akhgar, D. T. Smoot, M. Elbedawi, M. Daremipouran & A. Zhao

  2. Applied Statistics, Department of Natural Resource Sciences, University of Maryland, College Park, Maryland, USA

    B. Momen

  3. Department of Medicine, The Johns Hopkins University, Baltimore, Maryland, USA

    F. M. Giardiello

Authors
  1. H. Ashktorab
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. R. Begum
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. A. Akhgar
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. D. T. Smoot
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. M. Elbedawi
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. M. Daremipouran
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. A. Zhao
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. B. Momen
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. F. M. Giardiello
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to H. Ashktorab.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ashktorab, H., Begum, R., Akhgar, A. et al. Folate Status and Risk of Colorectal Polyps in African Americans. Dig Dis Sci 52, 1462–1470 (2007). https://doi.org/10.1007/s10620-006-9236-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-006-9236-8

Keywords