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Folate and Vitamin B6 Intake and Risk of Colon Cancer in Relation to p53 Expression

  • Eva S. Schernhammer
    Correspondence
    Address requests for reprints to: Eva S. Schernhammer, MD, DrPH, Channing Laboratory, 181 Longwood Avenue, Boston, Massachusetts 02115. fax: (617) 525-2008
    Affiliations
    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

    Ludwig Boltzmann Institute for Applied Cancer Research, KFJ-Spital, Vienna, Austria

    Applied Cancer Research - Institute for Translational Research Vienna, Vienna, Austria
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  • Shuji Ogino
    Affiliations
    Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
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  • Charles S. Fuchs
    Affiliations
    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
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      Background & Aims: Considerable evidence suggests that a low-folate diet increases the risk of colorectal cancer, although the results of a recent randomized trial indicate that folate supplementation may not reduce the risk of adenoma recurrence. In laboratory models, folate deficiency appears to induce p53 mutation. Methods: We immunohistochemically assayed p53 expression in paraffin-fixed colon cancer specimens in a large prospective cohort of women with 22 years of follow-up to examine the relationship of folate intake and intake of other one-carbon nutrients to risks by tumor p53 expression. Results: A total of 399 incident colon cancers accessible for p53 expression were available. The effect of folate differed significantly according to p53 expression (Pheterogeneity = .01). Compared with women reporting folate intake <200 μg/day, the multivariate relative risks (RRs) for p53-overexpressing (mutated) cancers were 0.54 (95% confidence interval [CI], 0.36–0.81) for women who consumed 200–299 μg/day, 0.42 (95% CI, 0.24–0.76) for women who consumed 300–399 μg/day, and 0.54 (95% CI, 0.35–0.83) for women who consumed ≥400 μg/day. In contrast, total folate intake had no influence on wild-type tumors (RR, 1.05; 95% CI, 0.73–1.51; comparing ≥400 with <200 μg/day). Similarly, high vitamin B6 intake conferred a protective effect on p53-overexpressing cancers (top versus bottom quintile: RR, 0.57; 95% CI, 0.35–0.94; Pheterogeneity = .01) but had no effect on p53 wild-type tumors. Conclusions: We found that low folate and vitamin B6 intake was associated with an increased risk of p53-overexpressing colon cancers but not wild-type tumors.

      Abbreviations used in this paper:

      CI (confidence interval), RR (relative risk)
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      References

        • Kim Y.I.
        Folate, colorectal carcinogenesis, and DNA methylation: lessons from animal studies.
        Environ Mol Mutagen. 2004; 44: 10-25
        • Giovannucci E.
        Epidemiologic studies of folate and colorectal neoplasia: a review.
        J Nutr. 2002; 132: 2350S-2355S
        • Harnack L.
        • Jacobs Jr, D.R.
        • Nicodemus K.
        • et al.
        Relationship of folate, vitamin B-6, vitamin B-12, and methionine intake to incidence of colorectal cancers.
        Nutr Cancer. 2002; 43: 152-158
        • Ulrich C.M.
        Folate and cancer prevention: a closer look at a complex picture.
        Am J Clin Nutr. 2007; 86: 271-273
        • Kim Y.I.
        • Shirwadkar S.
        • Choi S.W.
        • et al.
        Effects of dietary folate on DNA strand breaks within mutation-prone exons of the p53 gene in rat colon.
        Gastroenterology. 2000; 119: 151-161
        • Crott J.W.
        • Choi S.W.
        • Ordovas J.M.
        • et al.
        Effects of dietary folate and aging on gene expression in the colonic mucosa of rats: implications for carcinogenesis.
        Carcinogenesis. 2004; 25: 69-76
        • Sohn K.J.
        • Stempak J.M.
        • Reid S.
        • et al.
        The effect of dietary folate on genomic and p53-specific DNA methylation in rat colon.
        Carcinogenesis. 2003; 24: 81-90
        • Crott J.W.
        • Liu Z.
        • Keyes M.K.
        • et al.
        Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines.
        J Nutr Biochem. 2008; 19: 328-335
        • Crott J.W.
        • Liu Z.
        • Choi S.W.
        • et al.
        Folate depletion in human lymphocytes up-regulates p53 expression despite marked induction of strand breaks in exons 5–8 of the gene.
        Mutat Res. 2007; 626: 171-179
        • Wasson G.R.
        • McGlynn A.P.
        • McNulty H.
        • et al.
        Global DNA and p53 region-specific hypomethylation in human colonic cells is induced by folate depletion and reversed by folate supplementation.
        J Nutr. 2006; 136: 2748-2753
        • Vogelstein B.
        • Fearon E.R.
        • Hamilton S.R.
        • et al.
        Genetic alterations during colorectal-tumor development.
        N Engl J Med. 1988; 319: 525-532
        • Baker S.J.
        • Preisinger A.C.
        • Jessup J.M.
        • et al.
        p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis.
        Cancer Res. 1990; 50: 7717-7722
        • Hollstein M.
        • Rice K.
        • Greenblatt M.S.
        • et al.
        Database of p53 gene somatic mutations in human tumors and cell lines.
        Nucleic Acids Res. 1994; 22: 3551-3555
        • Giovannucci E.
        • Stampfer M.J.
        • Colditz G.A.
        • et al.
        Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study.
        Ann Intern Med. 1998; 129: 517-524
        • Chen J.
        • Giovannucci E.
        • Hankinson S.E.
        • et al.
        A prospective study of methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms, and risk of colorectal adenoma.
        Carcinogenesis. 1998; 19: 2129-2132
        • Willett W.C.
        • Sampson L.
        • Stampfer M.J.
        • et al.
        Reproducibility and validity of a semiquantitative food frequency questionnaire.
        Am J Epidemiol. 1985; 122: 51-65
        • Giovannucci E.
        • Stampfer M.J.
        • Colditz G.A.
        • et al.
        Folate, methionine, and alcohol intake and risk of colorectal adenoma.
        J Natl Cancer Inst. 1993; 85: 875-884
        • Willett W.C.
        • Sampson L.
        • Browne M.L.
        • et al.
        The use of a self-administered questionnaire to assess diet four years in the past.
        Am J Epidemiol. 1988; 127: 188-199
        • Willett W.C.
        • Stampfer M.J.
        • Colditz G.A.
        • et al.
        Moderate alcohol consumption and the risk of breast cancer.
        N Engl J Med. 1987; 316: 1174-1180
        • Stampfer M.J.
        • Willett W.C.
        • Speizer F.E.
        • et al.
        Test of the National Death Index.
        Am J Epidemiol. 1984; 119: 837-839
        • Melhem M.F.
        • Law J.C.
        • el-Ashmawy L.
        • et al.
        Assessment of sensitivity and specificity of immunohistochemical staining of p53 in lung and head and neck cancers.
        Am J Pathol. 1995; 146: 1170-1177
        • Nishio M.
        • Koshikawa T.
        • Kuroishi T.
        • et al.
        Prognostic significance of abnormal p53 accumulation in primary, resected non-small-cell lung cancers.
        J Clin Oncol. 1996; 14: 497-502
        • Greenblatt M.S.
        • Bennett W.P.
        • Hollstein M.
        • et al.
        Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis.
        Cancer Res. 1994; 54: 4855-4878
        • Ogino S.
        • Brahmandam M.
        • Kawasaki T.
        • et al.
        Combined analysis of COX-2 and p53 expressions reveals synergistic inverse correlations with microsatellite instability and CpG island methylator phenotype in colorectal cancer.
        Neoplasia. 2006; 8: 458-464
        • Camp R.L.
        • Charette L.A.
        • Rimm D.L.
        Validation of tissue microarray technology in breast carcinoma.
        Lab Invest. 2000; 80: 1943-1949
        • Ogino S.
        • Kawasaki T.
        • Kirkner G.J.
        • et al.
        Loss of nuclear p27 (CDKN1B/KIP1) in colorectal cancer is correlated with microsatellite instability and CIMP.
        Mod Pathol. 2007; 20: 15-22
        • Hall P.A.
        • McCluggage W.G.
        Assessing p53 in clinical contexts: unlearned lessons and new perspectives.
        J Pathol. 2006; 208: 1-6
        • Ogino S.
        • Brahmandam M.
        • Cantor M.
        • et al.
        Distinct molecular features of colorectal carcinoma with signet ring cell component and colorectal carcinoma with mucinous component.
        Mod Pathol. 2006; 19: 59-68
        • Curtin K.
        • Slattery M.L.
        • Holubkov R.
        • et al.
        p53 alterations in colon tumors: a comparison of SSCP/sequencing and immunohistochemistry.
        Appl Immunohistochem Mol Morphol. 2004; 12: 380-386
        • de Jong K.P.
        • Gouw A.S.
        • Peeters P.M.
        • et al.
        P53 mutation analysis of colorectal liver metastases: relation to actual survival, angiogenic status, and p53 overexpression.
        Clin Cancer Res. 2005; 11: 4067-4073
        • Hu F.B.
        • Stampfer M.J.
        • Rimm E.
        • et al.
        Dietary fat and coronary heart disease: a comparison of approaches for adjusting for total energy intake and modeling repeated dietary measurements.
        Am J Epidemiol. 1999; 149: 531-540
        • Lunn M.
        • McNeil D.
        Applying Cox regression to competing risks.
        Biometrics. 1995; 51: 524-532
        • Glynn R.J.
        • Rosner B.
        Comparison of risk factors for the competing risks of coronary heart disease, stroke, and venous thromboembolism.
        Am J Epidemiol. 2005; 162: 975-982
        • Durrleman S.
        • Simon R.
        Flexible regression models with cubic splines.
        Stat Med. 1989; 8: 551-561
        • Wei E.K.
        • Giovannucci E.
        • Selhub J.
        • et al.
        Plasma vitamin B6 and the risk of colorectal cancer and adenoma in women.
        J Natl Cancer Inst. 2005; 97: 684-692
        • Fuchs C.S.
        • Willett W.C.
        • Colditz G.A.
        • et al.
        The influence of folate and multivitamin use on the familial risk of colon cancer in women.
        Cancer Epidemiol Biomarkers Prev. 2002; 11: 227-234
        • Giovannucci E.
        • Rimm E.B.
        • Ascherio A.
        • et al.
        Alcohol, low-methionine–low-folate diets, and risk of colon cancer in men.
        J Natl Cancer Inst. 1995; 87: 265-273
        • Ulrich C.M.
        • Potter J.D.
        Folate supplementation: too much of a good thing?.
        Cancer Epidemiol Biomarkers Prev. 2006; 15: 189-193
        • Slattery M.L.
        • Curtin K.
        • Ma K.
        • et al.
        Diet activity, and lifestyle associations with p53 mutations in colon tumors.
        Cancer Epidemiol Biomarkers Prev. 2002; 11: 541-548
        • Lashner B.A.
        • Shapiro B.D.
        • Husain A.
        • et al.
        Evaluation of the usefulness of testing for p53 mutations in colorectal cancer surveillance for ulcerative colitis.
        Am J Gastroenterol. 1999; 94: 456-462
        • Ulrich C.M.
        • Potter J.D.
        Folate and cancer—timing is everything.
        JAMA. 2007; 297: 2408-2409
        • Cole B.F.
        • Baron J.A.
        • Sandler R.S.
        • et al.
        Folic acid for the prevention of colorectal adenomas: a randomized clinical trial.
        JAMA. 2007; 297: 2351-2359
        • Mason J.B.
        • Dickstein A.
        • Jacques P.F.
        • et al.
        A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis.
        Cancer Epidemiol Biomarkers Prev. 2007; 16: 1325-1329
        • Food and Drug Administration
        Food standards: amendment of standards of identity ro enriched grain products to require addition of folic acid.
        Fed Register. 1996; : 8797-8807
        • Ghavam-Nasiri M.R.
        • Rezaei E.
        • Ghafarzadegan K.
        • et al.
        Expression of p53 in colorectal carcinoma: correlation with clinicopathologic features.
        Arch Iran Med. 2007; 10: 38-42