Folate in colorectal cancer: beneficial or detrimental?

Altınay Altınkaynak; Hülya Kamarlı altun

doi:10.58625/jfng-3078

Authors

Altınay Altınkaynak Akdeniz University / Türkiye https://orcid.org/0000-0002-2012-2078
Hülya Kamarlı altun Akdeniz University / Türkiye https://orcid.org/0000-0001-9878-9297

DOI:

https://doi.org/10.58625/jfng-3078

Keywords:

Folate, folic acid, colorectal neoplasms, colonic neoplasms

Abstract

Folate is a water-soluble B-group vitamin found in various foods including green leafy vegetables, hens’ eggs, and legumes. Folate has an essential role in DNA repair, methylation, and synthesis. Folate deficiency causes neural tube defects, megaloblastic anemia, cardiovascular diseases, and cancer. Foods are enriched with folic acid, a synthetic monoglutamate form of folate, and folic acid supplementation is provided in many countries because the increased need for folate during pregnancy cannot be met only with food. Due to the important roles of folate in DNA synthesis, there are concerns that exposure to high doses of folic acid may cause colorectal cancer. Studies support that folic acid taken before polyp development has protective effects from colorectal cancer. On the other hand, folic acid supplementation induces colorectal cancer after polyp formation. It is also thought that epigenetic modifications affecting folate metabolism play a role in this process. In conclusion, folate intake at optimal levels and appropriate timing may exert protective effects against colorectal cancer, whereas folic acid consumed in supraphysiological doses and at later stages may promote tumor progression and increase the likelihood of carcinogenic progression of premalignant lesions.

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References

Qin, T., Du, M., Du, H., Shu, Y., Wang, M., & Zhu, L. (2015). Folic acid supplements and colorectal cancer risk: meta-analysis of randomized controlled trials, Scientific Reports, 5(1), 1-7. https://doi.org/10.1038/srep12044

Dekker, E., Tanis, P. J., Vleugels, J. L. A., Kasi, P. M., & Wallace, M. B. (2019). Colorectal cancer Lancet, 394(10207), 1467-1480. https://doi.org/10.1016/S0140-6736(19)32319-0

T.C. Sağlık Bakanlığı. (2022). Türkiye Kanser İstatistikleri 2017. https://hsgm.saglik.gov.tr/depo/birimler/kanser-db/Dokumanlar/Istatistikler/Turkiye_Kanser_Istatistikleri_2020.pdf

Keum, N., & Giovannucci, E. L. (2014). Folic acid fortification and colorectal cancer risk, American Journal of Preventive Medicine, 46(3), 65-72. https://doi.org/10.1016/j.amepre.2013.10.025.

Mousavi, S. M., Fallah, M., Sundquist, K., & Hemminki, K. (2012). Age- and time-dependent changes in cancer incidence among immigrants to Sweden: colorectal, lung, breast and prostate cancers, International Journal of Cancer, 131(2), 122-128. https://doi.org/10.1002/ijc.27334

Rebersek, M. (2021). Gut microbiome and its role in colorectal cancer, BMC Cancer, 21(1), 1325. https://doi.org/10.1186/s12885-021-09054-2

Winkels, R. M., Heine-Broring, R. C., van Zutphen, M., van Harten-Gerritsen, S., Kok, D. E., van Duijnhoven, F. J., & Kampman, E. (2014). The colon study: colorectal cancer: longitudinal, observational study on nutritional and lifestyle factors that may influence colorectal tumour recurrence, survival and quality of life, BMC Cancer, 14, 374. https://doi.org/10.1186/1471-2407-14-374

Wolf, A. M. D., Fontham, E. T. H., Church, T. R., Flowers, C. R., Guerra, C. E., LaMonte, S. J., ... & Smith, R. A. (2018). Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA: A Cancer Journal for Clinicians, 68(4), 250–281. https://doi.org/10.3322/caac.21457

Ifergan, I., & Assaraf, Y. G. (2008). Molecular mechanisms of adaptation to folate deficiency, Vitamins and Hormones, 79, 99-143. https://doi.org/10.1016/S0083-6729(08)00404-4

Zarou, M. M., Vazquez, A. & Vignir Helgason, G. (2021). Folate metabolism: a re-emerging therapeutic target in haematological cancers, Leukemia 35, 1539–1551. https://doi.org/10.1038/s41375-021-01189-2

Lee, Y., Vousden, K. H., Hennequart, M. (2024). Cycling back to folate metabolism in cancer, Nature Cancer., 5(5), 701-715. https://doi.org/10.1038/s43018-024-00739-8.

Fernández-Ramos, D., Lopitz-Otsoa F., Lu, S. C., Mato, J. M., (2025). S-Adenosylmethionine: A Multifaceted Regulator in Cancer Pathogenesis and Therapy, Cancers (Basel), 17(3), 535. doi: 10.3390/cancers17030535.

European Food Safety Authority. Folic acid: an update on scientific developments (Internet). EFSA Meeting Summary Report. (2009). https://www.efsa.europa.eu/sites/default/files/event/corporate090121-m.pdf

Ebara, S. (2017). Nutritional role of folate, Congenital Anomalies, 57(5), 138-141. https://doi.org/10.1111/cga.12233

Sanderson, P., McNulty, H., Mastroiacovo, P., McDowell, I. F., Melse-Boonstra, A., Finglas, P. M., & Gregory, J. F. (2003). Folate bioavailability: uk food standards agency workshop report, British Journal of Nutrition, 90(2), 473-479. https://doi.org/10.1079/bjn2003889

Konings, E. J., Roomans, H. H., Dorant, E., Goldbohm, R. A., Saris, W. H., & van den Brandt, P. A. (2001). Folate intake of the dutch population according to newly established liquid chromatography data for foods, The American Journal of Clinical Nutrition, 73(4), 765-776. https://doi.org/10.1093/ajcn/73.4.765

Kim, Y. I. (2007). Folate and colorectal cancer: an evidence-based critical review, Molecular Nutrition & Food Research, 51(3), 267-292. https://doi.org/10.1002/mnfr.200600191

Sanderson, P., Stone, E., Kim, Y. I., Mathers, J. C., Kampman, E., Downes, C. S., & Baron, J. A. (2007). Folate and colorectal cancer risk, British Journal of Nutrition, 98(6), 1299-1304. https://doi.org/10.1017/S0007114507771908

Hirsch, S., De la Maza, M. P., Barrera, G., Leiva, & L., Bunout, D. (2019). Folic acid and colon cancer: impact of wheat flour fortification with folic acid, Flour and Breads and their Fortification in Health and Disease Prevention, 2, 413-421. https://doi.org/10.1016/B978-0-12-814639-2.00032-0

Haas, C. B., Su, Y. R., Petersen, P., Wang, X., Bien, S. A., Lin, Y., Albanes, D., Weinstein, S. J., Jenkins, M. A., Figueiredo, J. C., Newcomb, P. A., Casey, G., Marchand, L. L., Campbell, P. T., Moreno, V., Potter, J. D., Sakoda, L. C., Slattery, M. L., Chan, A. T., Li, L., Giles, G. G., Milne, R. L., Gruber, S. B., Rennert, G., ... Hsu, L. (2022). Interactions between folate intake and genetic predictors of gene expression levels associated with colorectal cancer risk, Scientific Reports, 12(1), 18852. https://doi.org/10.1038/s41598-022-23451-y

Maynard, A. G., Petrova, B., & Kanarek, N. (2023). Notes from the 2022 folate, vitamin b12, and one-carbon metabolism conference, Metabolites, 13(4), 486. https://doi.org/10.3390/metabo13040486

Smith, A. D., Kim, Y. I., & Refsum, H. (2008). Is folic acid good for everyone? The American Journal of Clinical Nutrition, 87(3), 517-533. https://doi.org/10.1093/ajcn/87.3.517

Kennedy, D. A., Stern, S. J., & Koren, G. (2011). Folate intake and the risk of colorectal cancer: a systematic review and meta-analysis, Cancer Epidemiology, 35(1), 2-10. https://doi.org/10.1016/j.canep.2010.11.004

Nazki, F. H., Sameer, A. S., & Ganaie, B. A. (2014). Folate: metabolism, genes, polymorphisms and the associated diseases, Gene, 533(1), 11-20. https://doi.org/10.1016/j.gene.2013.09.063

Bailey, L. B., & Gregory, J. F. 3rd. (1999). Folate metabolism and requirements. Journal of Nutrition, 129(4), 779-782. https://doi.org/10.1093/jn/129.4.779

Kok, D. E., Steegenga, W. T., Smid, E. J., Zoetendal, E. G., Ulrich, C. M., & Kampman, E. (2020). Bacterial folate biosynthesis and colorectal cancer risk: more than just a gut feeling, Critical Reviews in Food Science and Nutrition, 60(2), 244-256. https://doi.org/10.1080/10408398.2018.1522499

T.C. Sağlık Bakanlığı. (2022). Türkiye Beslenme Rehberi (TÜBER). (Yayın No:103). https://ekutuphane.saglik.gov.tr/Yayin/683

Vipperla, K., & O’Keefe, S. J. (2013). Intestinal microbes, diet, and colorectal cancer, Current Colorectal Cancer Reports, 9(1), 95-105. https://doi.org/10.1007/s11888-012-0158-x

Arnold, M., Sierra, M. S., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2017). Global patterns and trends in colorectal cancer incidence and mortality, Gut, 66(4), 683-691. https://doi.org/10.1136/gutjnl-2015-310912

Akimoto, N., Ugai, T., & Ogino, S. (2021). Rising incidence of early-onset colorectal cancer - a call to action, Nature Reviews Clinical Oncology, 18(4), 230-243. https://doi.org/10.1038/s41571-020-00445-1

Morgan, E., Arnold, M., & Bray, F. (2023). Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN, Gut, 72(2), 338-344. https://doi.org/10.1136/gutjnl-2022-327736

Long, D., Mao, C., & Zhu, Y. (2023). Long-term trends in the burden of colorectal cancer in Europe over three decades: a joinpoint regression and age-period-cohort analysis, Frontiers in Oncology, 13, 1287653. https://doi.org/10.3389/fonc.2023.1287653

Thanikachalam, K., & Khan, G. (2019). Colorectal cancer and nutrition, Nutrients, 11(1). https://doi.org/10.3390/nu11010164

Veettil, S. K., Wong, T. Y., Loo, Y. S., Playdon, M. C., Lai, N. M., Giovannucci, E. L., & Chaiyakunapruk, N. (2021). Role of diet in colorectal cancer ıncidence: umbrella review of meta-analyses of prospective observational studies, JAMA Network, 4(2), e2037341. https://doi.org/10.1001/jamanetworkopen.2020.37341

Lin, K. J., Cheung, W. Y., Lai, J. Y., & Giovannucci, E. L. (2012). The effect of estrogen vs. combined estrogen-progestogen therapy on the risk of colorectal cancer, International Journal of Cancer, 130(2), 419-430. https://doi.org/10.1002/ijc.26026

Zheng, Y., Meng, L., & Li, M. (2022). Let food be thy medicine: the role of diet in colorectal cancer: a narrative review, Journal of Gastrointestinal Oncology, 13(4), 2020-2032. https://doi.org/10.21037/jgo-22-32

de las Peñas, R., Majem, M., Perez-Altozano, J., Virizuela, J. A., Cancer, E., Diz, P., Donnay, O., Hurtado, A., Jimenez-Fonseca, P., & Ocon, M. J. (2019). SEOM clinical guidelines on nutrition in cancer patients (2018), Clinical and Translational Oncology, 21(1), 87–93. https://doi.org/10.1007/S12094-018-02009-3/TABLES/2

Muscaritoli, M., Arends, J., Bachmann, P., Baracos, V., Barthelemy, N., Bertz, H., Bozzetti, F., Hütterer, E., Isenring, E., Kaasa, S., Krznaric, Z., Laird, B., Larsson, M., Laviano, A., Mühlebach, S., Oldervoll, L., Ravasco, P., Solheim, T. S., Strasser, F., … &Bischoff, S. C. (2021). ESPEN practical guideline: Clinical Nutrition in cancer, Clinical Nutrition, 40(5), 2898–2913. https://doi.org/10.1016/j.clnu.2021.02.005

Lewandowska, A., Religioni, U., Czerw, A., Deptała, A., Karakiewicz, B., Partyka, O., Pajewska, M., Sygit, K., Cipora, E., Kmieć, K., Augustynowicz, A., Mękal, D., Waszkiewicz, M., Barańska, A., Mináriková, D., Minárik, P., & Merks, P. (2022). Nutritional Treatment of Patients with Colorectal Cancer, In International Journal of Environmental Research and Public Health, 19, 11). https://doi.org/10.3390/ijerph19116881

Ravasco, P. (2019). Nutrition in Cancer Patients. Journal of Clinical Medicine 2019, 8(8), 1211. https://doi.org/10.3390/JCM8081211

Cancer Institute, N. (n.d.). Eating Hints: Before, during, and after Cancer Treatment Support for People with Cancer. https://www.cancer.gov/publications/patient-education/eating-hints

Van Blarigan, E. L., Fuchs, C. S., & Meyerhardt, A. J. (2018). Association of survival with adherence to the american cancer society nutrition and physical activity guidelines for cancer survivors after colon cancer diagnosis: the calgb 89803/alliance trial, JAMA Oncology, 4(6), 783-790. https://doi.org/10.1001/jamaoncol.2018.0126

Donaldson, G. P., Lee, S. M., & Mazmanian, S. K. (2016). Gut biogeography of the bacterial microbiota, Nature Reviews Microbiology, 14(1):20-32. https://doi.org/10.1038/nrmicro3552

Woo, H. D., & Kim, J. (2013). Dietary flavonoid intake and risk of stomach and colorectal cancer, World Journal of Gastroenterology, 19(7), 1011-1019. https://doi.org/10.3748/wjg.v19.i7.1011

Tilg, H., Adolph, T. E., Gerner, R. R., Moschen, A. R. (2018). The ıntestinal microbiota in colorectal cancer, Cancer Cell, 33(6), 954-964. https://doi.org/10.1016/j.ccell.2018.03.004.

Fidelle, M., Yonekura, S., & Zitvogel, L. (2020). Resolving the paradox of colon cancer through the integration of genetics, immunology, and the microbiota, Frontiers in Immunology, 14(11). https://doi.org/10.3389/fimmu.2020.600886

Gibson, T. M., Weinstein, & Stolzenberg-Solomon, R. (2011). Pre-and postfortification intake of folate and risk of colorectal cancer in a large prospective cohort study in the United States, The American Journal of Clinical Nutrition, 94(4), 1053-1062. https://doi.org/10.3945/ajcn.110.002659

Fu, H., He, J., Li, C., Deng, Z., & Chang, H. (2023). Folate intake and risk of colorectal cancer: a systematic review and up-to-date meta-analysis of prospective studies, European Journal of Cancer Prevention, 32(2), 103-112. https://doi.org/10.1097/CEJ.0000000000000744

Geijsen, A., Ulvik, A., Gigic, B., Kok, D. E., Van Duijnhoven, F. J. B., Holowatyj, A. N., Brezina, S., van Roekel, E. H., Baierl, A., Bergmann, M. M., Böhm, J., Bours, M. J. L., Brenner, H., Breukink, S., Bronner, M. P., Chang-Claude, J., de Wilt, J. H. W., Grünberger, T, Grady, W. M., ... Kampman, E. (2020). Circulating folate and folic acid concentrations: associations with colorectal cancer recurrence and survival, JNCI Cancer Spectrum, 4(5), 051. https://doi.org/10.1093/jncics/pkaa051

Cole, B. F., Baron, J. A., Sandler, R. S., Haile, R. W., Ahnen, D. J., Bresalier, R. S., McKeown-Eyssen, G., Summers, R. W., Rothstein, R. I., Burke, C. A., Snover, D. C., Church, T. R., Allen, J. I., Robertson, D. I., Beck, G. J., Bond, J. H., Byers, T., Mandel, J. S., Mott, L. A., Pearson, L. H., … Greenberg, E. (2007). Folic acid for the prevention of colorectal adenomas: a randomized clinical trial, JAMA, 297(21), 2351-2359. https://doi.org/10.1001/jama.297.21.2351

Huang, C. Y., Abulimiti, A., & Zhang, C. X. (2020). Dietary B vitamin and methionine intakes and risk for colorectal cancer: a case–control study in China, British Journal of Nutrition, 123(11), 1277-1289. https://doi.org/10.1017/S0007114520000501

Wang, F., Wu, K., & Willet, W. C. (2021). Association of folate intake and colorectal cancer risk in the postfortification era in US women, The American Journal of Clinical Nutrition, 114(1), 49-58. https://doi.org/10.1093/ajcn/nqab035

Çakıcı, V., Yorulmaz, E., & Şenateş, E. (2014). Mide ve kolon kanserlerinde metastaz göstergesi olarak serum folat ve vitamin B12 düzeylerinin değerlendirilmesi, Endoskopi Gastrointestinal, 22(2), 25-28. https://doi.org/10.17940/endoskopi.74778

Gylling, B., Van Guelpen, B., & Palmqvist, R. (2014). Low folate levels are associated with reduced risk of colorectal cancer in a population with low folate status, Cancer Epidemiology, Biomarkers & Prevention, 23(10), 2136-2144. https://doi.org/10.1158/1055-9965.EPI-13-1352

Cho, E., Zhang, X., & Giovannuci, E. L. (2015). Unmetabolized folic acid in prediagnostic plasma and the risk for colorectal cancer, Journal of the National Cancer Institute, 107(12), 260. https://doi.org/10.1093/jnci/djv260

Moazzen, S., Dolatkhah, R., & Dastgiri, S. (2018). Folic acid intake and folate status and colorectal cancer risk: a systematic review and meta-analysis, Clinical Nutrition, 37(6), 1926-1934. https://doi.org/10.1016/j.clnu.2017.10.010

T.C. Sağlık Bakanlığı. (2019). Türkiye Beslenme ve Sağlık Araştırması (TBSA). (Yayın No:1132). https://hsgm.saglik.gov.tr/depo/birimler/saglikli-beslenme-ve-hareketli-hayat-db/Dokumanlar/Kitaplar/Turkiye_Beslenme_ve_Saglik_Arastirmasi_TBSA_2017.pdf

Wald, N. J. (2022). Folic acid and neural tube defects: Discovery, debate and the need for policy change, Journal of Medical Screening, 29(3), 138-146. https://doi.org/10.1177/09691413221102321

Passarelli, M. N., Barry, E. L., & Baron, J. A. (2019). Folic acid supplementation and risk of colorectal neoplasia during long-term follow-up of a randomized clinical trial, The American Journal of Clinical Nutrition, 110(4), 903-911. https://doi.org/10.1093/ajcn/nqz160

Vollset, S. E., Clarke, R., Lewington, S., Ebbing, M., Halsey, J., Lonn, E., Armitage, J., Manson, J. E., Hankey, G. J., Spence, J. D., Galan, P., Boanna, K. H., Jamison, R., Gaziano, J. M., Guarino, P., Baron, A., Logan, R. F. A., Giovannuci, E. L., Heijer, M., … Peto, R. (2013). Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals, Lancet, 381(9871), 1029-1036. https://doi.org/10.1016/S0140-6736(12)62001-7

Mason, J. B. (2021). Folate and colon cancer: dietary habits from the distant past coming home to roost, The American Journal of Clinical Nutrition, 114(1), 1-2. https://doi.org/10.1093/ajcn/nqab117.

Steluti, J., Miranda, A. M., De Carli, E., Palchetti, C. Z., Fisberg, R. M., & Marchioni, D. M. L. (2021). Unmetabolized folic acid is associated with TNF-α, IL-1β and IL-12 concentrations in a population exposed to mandatory food fortification with folic acid: a cross-sectional population-based study in Sao Paulo, Brazil, European Journal of Clinical Nutrition, 60(2), 1071-1079. https://doi.org/10.1007/s00394-020-02307-z

Shen, Y. (2025). The Dual Role of Folate Metabolism in Colorectal Cancer: Bridging Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms, Molecular Subtypes and Precision Prevention, Current Science, 5(2), 1446-1454. https://doi.org/10.52845/CS/2025-5-2-13

Rodríguez Silva, J., Monsalves-Álvarez, M., Sepúlveda, C., Donoso-Barraza, C., troncoso, R., & Hirsch, S. (2025) Folate induces stemness and increases oxygen consumption under glucose deprivation by notch-1 pathway activation in colorectal cancer cell, Molecular and Cell Biochemistry, 480, 505–519. https://doi.org/10.1007/s11010-024-04987-1

Reynolds, E. H. (2016). What is the safe upper intake level of folic acid for the nervous system? Implications for folic acid fortification policies, European Journal of Clinical Nutrition, 70(5), 537-540. https://doi.org/10.1038/ejcn.2015.231

Florescu, D. N., Boldeanu, M. V., Șerban, R.-E., Florescu, L. M., Serbanescu, M.-S., Ionescu, M., Streba, L., Constantin, C., & Vere, C. C. (2023). Correlation of the Pro-Inflammatory Cytokines IL-1β, IL-6, and TNF-α, Inflammatory Markers, and Tumor Markers with the Diagnosis and Prognosis of Colorectal Cancer. Life, 13(12), 2261. https://doi.org/10.3390/life13122261

Mirlekar, B., & Pylayeva-Gupta, Y. (2021). IL-12 Family Cytokines in Cancer and Immunotherapy, Cancers, 13(2), 167. https://doi.org/10.3390/cancers13020167

Pfeiffer, C. M., Sternberg, &Johnson, C. L. (2015). Unmetabolized folic acid is detected in nearly all serum samples from US children, adolescents, and adults, Journal of Nutrition, 145(3), 520-531. https://doi.org/10.3945/jn.114.201210

Plumptre, L., Masih, & Kim, Y. I. (2015). High concentrations of folate and unmetabolized folic acid in a cohort of pregnant Canadian women and umbilical cord blood, The American Journal of Clinical Nutrition,102(4), 848-857. https://doi.org/10.3945/ajcn.115.110783

Teng, Z., Wang, L., Cai, S., Yu, P., Wang, J., Gong, J., & Liu, Y. (2013). The 677C> T (rs1801133) polymorphism in the MTHFR gene contributes to colorectal cancer risk: a meta-analysis based on 71 research studies, PloS one, 8(2), e55332. https://doi.org/10.1371/journal.pone.0055332

Kennedy, D. A. Stern SJ, Matok I, Moretti ME, Sarkar M, Adams-Webber T, & Koren G. (2012). Folate intake, MTHFR polymorphisms, and the risk of colorectal cancer: A systematic review and meta‐analysis, Journal of Cancer Epidemiology, 1, 952508. https://doi.org/10.1155/2012/952508

Zhang, Z., Xu, L., Huang, L., Li, T., Wang, . J. Y., Ma, C., Bian, X., Ren, X., Li, H., Wang, X. (2022) Glutathione S-Transferase Alpha 4 Promotes Proliferation and Chemoresistance in Colorectal Cancer Cells, Frontiers in Oncology, 1, 12, 887127. https://doi.org/10.3389/fonc.2022.887127

Banning, A., Laine, M., & Tikkanen, R. (2023). Validation of aspartylglucosaminidase activity assay for human serum samples: establishment of a biomarker for diagnostics and clinical studies. International Journal of Molecular Sciences, 24(6), 5722. https://doi.org/10.3390/ijms24065722

Robien, K. (2005). Folate during antifolate chemotherapy: what we know... and do not know, Nutrition in Clinical Practice, 20(4), 411-22. https://doi.org/ 10.1177/0115426505020004411

Glimelius, B., Stintzing, S., Marshall, J., Yoshino, T., & de Gramont, A. (2021). Metastatic colorectal cancer: advances in the folate-fluoropyrimidine chemotherapy backbone, Cancer Treatment Reviews, 98, 102218. https://doi.org/10.1016/j.ctrv.2021.102218

National Comprehensive Cancer Network. (2024). Colon cancer: NCCN guidelines for patients. https://www.nccn.org/patients/guidelines/content/PDF/colon-patient.pdf

Zwart, N. R., Franken, M. D., Tissing, W. J., Lubberman, F. J., Mckay, J. A., Kampman, E., Kok, D. E. (2023). Folate, folic acid, and chemotherapy-induced toxicities: A systematic literature review, Critical Reviews in Oncology/Hematology, 188, 104061. https://doi.org/10.1016/j.critrevonc.2023.104061