Folate in colorectal cancer: beneficial or detrimental?

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.

Keywords

• Folate
• folic acid
• colorectal cancer
• colonic neoplasms

Kolorektal kanserde folat: yararlı mı, zararlı mı?

Abstract

Folat yeşil yapraklı sebzeler, yumurta ve baklagiller gibi birçok besinde bulunan suda çözünen bir B grubu vitamini olarak kabul edilmektedir. DNA onarımı, metilasyonu ve sentezi gibi önemli rolleri bulunur. Eksikliğinde nöral tüp defekti, megaloblastik anemi, kardiyovasküler hastalıklar ve kanser gibi hastalıklar görülmektedir. Özellikle gebelik döneminde ihtiyacın artması ve bunun besinlerle sağlanamamasından ötürü birçok ülkede besinler folatın sentetik monoglutamat formu olan folik asitle zenginleştirilmektedir ve folik asit takviyesi sağlanmaktadır. DNA sentezindeki önemli rollerinden dolayı yüksek doz folik asite maruziyetin kolorektal kansere neden olabileceğine dair endişeler de mevcuttur. Yapılan araştırmalar polip oluşumundan önce alınan folik asidin kolorektal kanserden koruyucu etkileri olduğunu desteklemekte ancak polip oluşumundan sonra kolorektal kanser gelişimini indüklediğini ortaya koymaktadır. Ayrıca folat metabolizmasını etkileyen epigenetik modifikasyonların da bu süreçte etkili olduğu düşünülmektedir. Sonuç olarak, optimal düzeylerde ve doğru zamanda alınan folat, kolorektal kanser riskini azaltıcı etkilere sahipken; fizyolojik sınırların üzerinde ve geç dönemde alınan folik asit, tümör progresyonunu destekleyebilir ve premalign lezyonların kansere dönüşme riskini artırabilir.

Keywords

• Folat
• folik asit
• kolorektal kanser
• kolon neoplazmları

References

1. Referans1. 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
2. Referans2. 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
3. Referans3. 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
4. Referans4. 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.
5. Referans5. 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
6. Referans6. 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
7. Referans7. 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
8. Referans8. 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

9. Referans9. 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
10. Referans10. 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
11. Referans11. 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.
12. Referans12. 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.
13. Referans13. 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
14. Referans14. Ebara, S. (2017). Nutritional role of folate, Congenital Anomalies, 57(5), 138-141. https://doi.org/10.1111/cga.12233
15. Referans15. 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
16. Referans16. 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
17. Referans17. 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
18. Referans18. 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
19. Referans19. 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
20. Referans20. 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
21. Referans21. 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
22. Referans22. 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
23. Referans23. 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
24. Referans24. 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
25. Referans25. 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
26. Referans26. 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
27. Referans27. T.C. Sağlık Bakanlığı. (2022). Türkiye Beslenme Rehberi (TÜBER). (Yayın No:103). https://ekutuphane.saglik.gov.tr/Yayin/683
28. Referans28. 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
29. Referans29. 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
30. Referans30. 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
31. Referans31. 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
32. Referans32. 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
33. Referans33. Thanikachalam, K., & Khan, G. (2019). Colorectal cancer and nutrition, Nutrients, 11(1). https://doi.org/10.3390/nu11010164
34. Referans34. 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
35. Referans35. 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
36. Referans36. 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
37. Referans37. 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
38. Referans38. 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
39. Referans39. 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
40. Referans40. Ravasco, P. (2019). Nutrition in Cancer Patients. Journal of Clinical Medicine 2019, 8(8), 1211. https://doi.org/10.3390/JCM8081211
41. Referans41. 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
42. Referans42. 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
43. Referans43. 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
44. Referans44. 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
45. Referans45. 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.
46. Referans46. 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
47. Referans47. 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
48. Referans48. 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
49. Referans49. 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
50. Referans50. 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
51. Referans51. 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
52. Referans52. 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
53. Referans53. 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
54. Referans54. 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
55. Referans55. 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
56. Referans56. 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
57. Referans57. 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
58. Referans58. 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
59. Referans59. 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
60. Referans60. 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
61. Referans61. 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.
62. Referans62. 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
63. Referans63. 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
64. Referans64. 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
65. Referans65. 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
66. Referans66. 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
67. Referans67. Mirlekar, B., & Pylayeva-Gupta, Y. (2021). IL-12 Family Cytokines in Cancer and Immunotherapy, Cancers, 13(2), 167. https://doi.org/10.3390/cancers13020167
68. Referans68. 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
69. Referans69. 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
70. Referans70. 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
71. Referans71. 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
72. Referans72. 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
73. Referans73. 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
74. Referans74. 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
75. Referans75. 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
76. Referans76. National Comprehensive Cancer Network. (2024). Colon cancer: NCCN guidelines for patients. https://www.nccn.org/patients/guidelines/content/PDF/colon-patient.pdf
77. Referans77. 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