Prostate cancer (PC) is the second leading cause of cancer death in men. Recent reports suggest that excess of nutrients involved in the one-carbon metabolism pathway increases PC risk; however, empirical data are lacking. Veteran American men (272 controls and 144 PC cases) who attended the Durham Veteran American Medical Center between 2004–2009 were enrolled into a case-control study. Intake of folate, vitamin B12, B6, and methionine were measured using a food frequency questionnaire. Regression models were used to evaluate the association among one-carbon cycle nutrients, MTHFR genetic variants, and prostate cancer. Higher dietary methionine intake was associated with PC risk (OR = 2.1; 95%CI 1.1–3.9) The risk was most pronounced in men with Gleason sum <7 (OR = 2.75; 95%CI 1.32– 5.73). The association of higher methionine intake and PC risk was only apparent in men who carried at least one MTHFR A1298C allele (OR = 6 . 7 ; 95%CI = 1.6–27.8), compared to MTHFR A1298A noncarrier men (OR = 0 . 9 ; 95%CI = 0.24–3.92) (p-interaction = 0 . 0 4 5 ). There was no evidence for associations between B vitamins (folate, B12, and B6) and PC risk. Our results suggest that carrying the MTHFR A1298C variants modifies the association between high methionine intake and PC risk. Larger studies are required to validate these findings. 1. Introduction Prostate cancer (PC) is the most commonly diagnosed malignancy in men, and the second leading cause of cancer death in men globally [1]. Age adjusted PC incidence and mortality exhibits considerable geographic and racial variation, suggesting that both heritable and environmentally acquired/dietary factors are important [2, 3]. Regarding dietary factors, either deficiencies or excesses of nutrients involved in the one-carbon metabolism pathway have been hypothesized to increase PC risk, but findings are inconsistent [4–15]. The one-carbon cycle is necessary for both cellular proliferation and epigenetic modification and folate is a critical component of this pathway. Folate functions as an important source of carbon moieties in the synthesis of nucleotides that are essential for DNA repair and replication. The important role of folate is illustrated by the mutations and chromosomal damage associated with its deficiency. These effects are central to the efficacy of antifolate chemotherapeutic agents (e.g., methotrexate) as tumor therapeutics. Folate is also essential in the conversion of methionine to its derivative, S-adenosylmethionine, the principal methyl donor [16], which transfers methyl groups to molecules key for
References
[1]
J. Ferlay, H. R. Shin, F. Bray, D. Forman, C. Mathers, and D. M. Parkin, “Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008,” International Journal of Cancer, vol. 127, no. 12, pp. 2893–2917, 2010.
[2]
H. Gr？nberg, “Prostate cancer epidemiology,” The Lancet, vol. 361, no. 9360, pp. 859–864, 2003.
[3]
L. E. Johns and R. S. Houlston, “A systematic review and meta-analysis of familial prostate cancer risk,” BJU International, vol. 91, no. 9, pp. 789–794, 2003.
[4]
C. Pelucchi, C. Galeone, R. Talamini et al., “Dietary folate and risk of prostate cancer in Italy,” Cancer Epidemiology Biomarkers and Prevention, vol. 14, no. 4, pp. 944–948, 2005.
[5]
J. C. Figueiredo, M. V. Grau, R. W. Haile et al., “Folic acid and risk of prostate cancer: results from a randomized clinical trial,” Journal of the National Cancer Institute, vol. 101, no. 6, pp. 432–435, 2009.
[6]
S. J. Weinstein, T. J. Hartman, R. Stolzenberg-Solomon et al., “Null association between prostate cancer and serum folate, vitamin b 6, vitamin b12, and homocysteine,” Cancer Epidemiology Biomarkers and Prevention, vol. 12, no. 11, pp. 1271–1272, 2003.
[7]
B. R. Van Guelpen, S. M. Wirén, A. R. J. Bergh, G. Hallmans, P. E. Stattin, and J. Hultdin, “Polymorphisms of methylenetetrahydrofolate reductase and the risk of prostate cancer: a nested case-control study,” European Journal of Cancer Prevention, vol. 15, no. 1, pp. 46–50, 2006.
[8]
J. Hultdin, B. Van Guelpen, A. Bergh, G. Hallmans, and P. Stattin, “Plasma folate, vitamin B12, and homocysteine and prostate cancer risk: a prospective study,” International Journal of Cancer, vol. 113, no. 5, pp. 819–824, 2005.
[9]
M. Johansson, P. N. Appleby, N. E. Allen et al., “Circulating concentrations of folate and vitamin B12 in relation to prostate cancer risk: results from the European prospective investigation into cancer and nutrition study,” Cancer Epidemiology Biomarkers and Prevention, vol. 17, no. 2, pp. 279–285, 2008.
[10]
T. Key, P. B. Silcocks, G. K. Davey, P. N. Appleby, and D. T. Bishop, “A case-control study of diet and prostate cancer,” British Journal of Cancer, vol. 76, no. 5, pp. 678–687, 1997.
[11]
H. D. Vlajinac, J. M. Marinkovi？, M. D. Ili？, and N. I. Kocev, “Diet and prostate cancer: a case-control study,” European Journal of Cancer Part A, vol. 33, no. 1, pp. 101–107, 1997.
[12]
V. L. Stevens, C. Rodriguez, A. L. Pavluck, M. L. McCullough, M. J. Thun, and E. E. Calle, “Folate nutrition and prostate cancer incidence in a large cohort of US men,” American Journal of Epidemiology, vol. 163, no. 11, pp. 989–996, 2006.
[13]
S. J. Weinstein, R. Stolzenberg-Solomon, P. Pietinen, P. R. Taylor, J. Virtamo, and D. Albanes, “Dietary factors of one-carbon metabolism and prostate cancer risk,” American Journal of Clinical Nutrition, vol. 84, no. 4, pp. 929–935, 2006.
[14]
E. Rossi, J. Hung, J. P. Beilby, M. W. Knuiman, M. L. Divitini, and H. Bartholomew, “Folate levels and cancer morbidity and mortality: prospective cohort study from Busselton, Western Australia,” Annals of Epidemiology, vol. 16, no. 3, pp. 206–212, 2006.
[15]
J. Shannon, E. Phoutrides, A. Palma et al., “Folate intake and prostate cancer risk: a case-control study,” Nutrition and Cancer, vol. 61, no. 5, pp. 617–628, 2009.
[16]
S. J. Duthie, “Folic acid deficiency and cancer: mechanisms of DNA instability,” British Medical Bulletin, vol. 55, no. 3, pp. 578–592, 1999.
[17]
M. Fenech, “The role of folic acid and Vitamin B12 in genomic stability of human cells,” Mutation Research, vol. 475, no. 1-2, pp. 57–67, 2001.
[18]
B. T. Heijmans, J. M. A. Boer, H. E. D. Suchiman et al., “A common variant of the methylenetetrahydrofolate reductase gene (1p36) is associated with an increased risk of cancer,” Cancer Research, vol. 63, no. 6, pp. 1249–1253, 2003.
[19]
S. J. Duthie, G. Horgan, B. de Roos et al., “Blood folate status and expression of proteins involved in immune function, inflammation, and coagulation: biochemical and proteomic changes in the plasma of humans in response to long-term synthetic folic acid supplementation,” Journal of Proteome Research, vol. 9, no. 4, pp. 1941–1950, 2010.
[20]
P. A. Jones and S. B. Baylin, “The fundamental role of epigenetic events in cancer,” Nature Reviews Genetics, vol. 3, no. 6, pp. 415–428, 2002.
[21]
T. Keku, R. Millikan, K. Worley et al., “5,10-Methylenetetrahydrofolate reductase codon 677 and 1298 polymorphisms and colon cancer in African Americans and whites,” Cancer Epidemiology Biomarkers and Prevention, vol. 11, no. 12, pp. 1611–1621, 2002.
[22]
M. Lucock, “Science, medicine, and the future: is folic acid the ultimate functional food component for disease prevention?” British Medical Journal, vol. 328, no. 7433, pp. 211–214, 2004.
[23]
J. B. Mason, “Folate, cancer risk, and the Greek god, Proteus: a tale of two chameleons,” Nutrition Reviews, vol. 67, no. 4, pp. 206–212, 2009.
[24]
S. M. Zhang, W. C. Willett, J. Selhub et al., “Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer,” Journal of the National Cancer Institute, vol. 95, no. 5, pp. 373–380, 2003.
[25]
U. Ericson, S. Borgquist, M. I. L. Ivarsson et al., “Plasma folate concentrations are positively associated with risk of estrogen receptor β negative breast cancer in a Swedish nested case control study,” Journal of Nutrition, vol. 140, no. 9, pp. 1661–1668, 2010.
[26]
B. F. Cole, J. A. Baron, R. S. Sandler et al., “Folic acid for the prevention of colorectal adenomas: a randomized clinical trial,” Journal of the American Medical Association, vol. 297, no. 21, pp. 2351–2359, 2007.
[27]
C. M. Pfeiffer, S. P. Caudill, E. W. Gunter, J. Osterloh, and E. J. Sampson, “Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999–2000,” American Journal of Clinical Nutrition, vol. 82, no. 2, pp. 442–450, 2005.
[28]
E. A. Yetley, C. M. Pfeiffer, K. W. Phinney et al., “Biomarkers of folate status in NHANES: a roundtable summary1–6,” American Journal of Clinical Nutrition, vol. 94, no. 1, pp. 303S–312S, 2011.
[29]
C. M. Ulrich, J. D. Potter, and N. Ulrich, “Folate supplementation: too much of a good thing?” Cancer Epidemiology Biomarkers and Prevention, vol. 15, no. 2, pp. 189–193, 2006.
[30]
A. D. Smith, Y. I. Kim, and H. Refsum, “Is folic acid good for everyone?” American Journal of Clinical Nutrition, vol. 87, no. 3, pp. 517–533, 2008.
[31]
J. B. Mason, A. Dickstein, P. F. Jacques 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 Epidemiology Biomarkers and Prevention, vol. 16, no. 7, pp. 1325–1329, 2007.
[32]
S. M. Collin, C. Metcalfe, L. Zuccolo et al., “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 Epidemiology Biomarkers and Prevention, vol. 18, no. 9, pp. 2528–2539, 2009.
[33]
J. A. Antonelli, L. W. Jones, L. L. Ba？ez et al., “Exercise and prostate cancer risk in a cohort of veterans undergoing prostate needle biopsy,” Journal of Urology, vol. 182, no. 5, pp. 2226–2231, 2009.
[34]
C. D. Williams, B. M. Whitley, C. Hoyo et al., “A high ratio of dietary n-6/n-3 polyunsaturated fatty acids is associated with increased risk of prostate cancer,” Nutrition Research, vol. 31, no. 1, pp. 1–8, 2011.
[35]
J. A. Roebuck Jr., Anthropometric Methods: Designing To Fit the Human Body, Human Factor and Ergonomics Society, Santa Monica, Calif, USA, 1995.
[36]
W. C. Willet, L. Sampson, M. J. Stampfer et al., “Reproducibility and validity of a semiquantitative food frequency questionnaire,” American Journal of Epidemiology, vol. 122, no. 1, pp. 51–65, 1985.
[37]
C. F. Adams, Nutritive Value of American Foods, vol. 456, United States Department of Agriculture, 1975.
[38]
R. M. Feeley, P. E. Criver, and B. K. Watt, “Cholesterol content of foods,” Journal of the American Dietetic Association, vol. 61, no. 2, pp. 134–149, 1972.
[39]
P. J. McLaughlin and J. L. Weihrauch, “Vitamin E content of foods,” Journal of the American Dietetic Association, vol. 75, no. 6, pp. 647–665, 1979.
[40]
S. Bettuzzi, M. Brausi, F. Rizzi, G. Castagnetti, G. Peracchia, and A. Corti, “Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study,” Cancer Research, vol. 66, no. 2, pp. 1234–1240, 2006.
[41]
P. M. Das and R. Singal, “DNA methylation and cancer,” Journal of Clinical Oncology, vol. 22, no. 22, pp. 4632–4642, 2004.
[42]
W. H. Lee, W. B. Isaacs, G. Steven Bova, and W. G. Nelson, “CG island methylation changes near the GSTP1 gene in prostatic carcinoma cells detected using the polymerase chain reaction: A new prostate cancer biomarker,” Cancer Epidemiology Biomarkers and Prevention, vol. 6, no. 6, pp. 443–450, 1997.
[43]
X. Shan, L. Wang, R. Hoffmaster, and W. D. Kruger, “Functional characterization of human methylenetetrahydrofolate reductase in Saccharomyces cerevisiae,” Journal of Biological Chemistry, vol. 274, no. 46, pp. 32613–32618, 1999.
[44]
R. A. Waterland, “Assessing the effects of high methionine intake on DNA methylation,” Journal of Nutrition, vol. 136, no. 6, 2006.
[45]
A. P. Feinberg, R. Ohlsson, and S. Henikoff, “The epigenetic progenitor origin of human cancer,” Nature Reviews Genetics, vol. 7, no. 1, pp. 21–33, 2006.
[46]
J. J. Tomaszewski, J. L. Cummings, A. V. Parwani et al., “Increased cancer cell proliferation in prostate cancer patients with high levels of serum folate,” Prostate, vol. 71, no. 12, pp. 1287–1293, 2011.
[47]
C. Marchal, M. Redondo, A. Reyes-Engel et al., “Association between polymorphisms of folate-metabolizing enzymes and risk of prostate cancer,” European Journal of Surgical Oncology, vol. 34, no. 7, pp. 805–810, 2008.
[48]
J. Chen, J. Ma, M. J. Stampfer, C. Palomeque, J. Selhub, and D. J. Hunter, “Linkage disequilibrium between the 677C→t and 1298A→C polymorphisms in human methylenetetrahydrofolate reductase gene and their contributions to risk of colorectal cancer,” Pharmacogenetics, vol. 12, no. 4, pp. 339–342, 2002.
[49]
S. Ogino and R. B. Wilson, “Genotype and haplotype distributions of MTHFR677C→T and 1298A→C single nucleotide polymorphisms: a meta-analysis,” Journal of Human Genetics, vol. 48, no. 1, pp. 1–7, 2003.
[50]
N. Rosenberg, M. Murata, Y. Ikeda, O. Opare-Sem, E. Geffen, and U. Seligsohn, “The frequent 5, 10-methylenetetrahydrofolate reductase C677T polymorphism is associated with a common haplotype in Whites, Japanese, and Africans,” , American Journal of Human Genetics, vol. 70, no. 3, pp. 758–762, 2002.
[51]
M. S. Cicek, N. L. Nock, L. Li, D. V. Conti, G. Casey, and J. S. Witte, “Relationship between methylenetetrahydrofolate reductase C677T and A1298C genotypes and haplotypes and prostate cancer risk and aggressiveness,” Cancer Epidemiology, Biomarkers & Prevention, vol. 13, no. 8, pp. 1331–1336, 2004.
[52]
V. L. Stevens, C. Rodriguez, J. Sun, J. T. Talbot, M. J. Thun, and E. E. Calle, “No association of SNPs in one-carbon metabolism genes with prostate cancer risk,” Cancer Epidemiology, Biomarkers & Prevention, vol. 17, no. 12, pp. 3612–3614, 2008.
[53]
P. Frost, H. J. Blom, P. Gollete, C. A. Sephhard, and R. G. Matthews, “A candidate genetic risk factor for vascular disease,” Nature Genetics, vol. 10, no. 24, pp. 111–113, 1995.
[54]
N. M. Van der Put, F. Gabreels, E. M. Stevens et al., “A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defect?” American Journal of Human Genetics, vol. 62, no. 5, pp. 1044–1051, 1998.
[55]
J. Summer, D. A. Jencks, S. Khani, and R. G. Matthews, “Photoaffinity labeling of methylnetetrahydrofolate reductase with 8-azido-S-adenosylmethionine,” Journal of Biological Chemistry, vol. 261, no. 17, pp. 7697–7700, 1986.
[56]
G. Corona, G. Toffoli, M. Fabris et al., “Homocysteine accumulation in human ovarian carcinoma ascetic/cystic fluids possibly caused by metabolic alteration of the methionine cycle in , ovarian carcinoma cells,” European Journal of Cancer, vol. 33, no. 8, pp. 1284–1290, 1997.
[57]
J. Lin, I. M. Lee, Y. Song et al., “Plasma homocysteine and cysteine and risk of breast cancer in women,” Cancer Research, vol. 70, no. 6, pp. 2397–2405, 2010.
[58]
C. M. Ulrich, E. Kampman, J. Bigler et al., “Colorectal adenomas and the C677T MTHFR polymorphism: evidence for gene-environment interaction?” Cancer Epidemiology, Biomarkers & Prevention, vol. 8, no. 8, pp. 659–668, 1999.
[59]
H. Refsum, P. M. Ueland, O. Nygard, and S. E. Vollset, “Homocysteine and cardiovascular disease,” Annual Reviews, vol. 49, pp. 31–62, 1998.
