FOLATE AND CANCER: A POSITIVE, NEGATIVE OR NEUTRAL RELATIONSHIP?
OLOKO KOFOWOROLA RAFIAT
DOKITA Editorial Board Member
The relationship between folate and cancer is uncertain; several studies, intervention trials have been done to review their relationship. The studies demonstrated positive, negative and neutral relationships. However, many factors contributed to the relationships demonstrated.
So, this paper summarises the various relationships that exist between folate and cancer risk, and also the factors that permits these associations. The findings here are supported reviews of meta-analyses from the past 5 years. The factors that contribute to the association between folate and cancer risk are timing and dosage of vitamin, type of vitamin (dietary, supplemental and total), cancer type and folate intake, serum levels and evaluation methods, and gene polymorphisms.
WHAT IS FOLATE AND FOLIC ACID?
Folate is an essential B vitamin found in fruits, vegetables (especially the dark green leafy vegetables), legumes, and some meats. The active form of the vitamin is 5-methyltetrahydrofolate, which is essential for the transfer of one-carbon units involved in nucleotide biosynthesis and biological methylations.1 5-Methyltetrahydrofolate (5-MTHF) and cobalamin are required for the conversion of homocysteine to methionine in the methionine pathway. Methionine is converted to S-adenosylmethionine (SAM). SAM is a chief methyl contributor to many reactions in the body, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) methylation. So, in folate deficiency, SAM is reduced, and synthesis, methylation and repair of DNA are impaired thereby increasing the risk of cancer development.2
Folic acid (pteroylmonoglutamic acid) is a fully oxidised folate, with chemical structure consisting of pteridine, para aminobenzoic acid, and glutamic acid. It is found in many multivitamin and prenatal vitamin supplements, fortified foods and in standard B vitamin supplements.3 Folic acid is converted to tetrahydrofolate in the liver by dihydrofolate reductase (DHFR). According to some reports, folic acid greater than 400 mcg can saturate the DHFR enzyme, resulting in unreduced folic acid, which has been proposed has a potent carcinogenic mechanism.4
For adults, the recommended dietary intake is 400 micrograms (mcg) of dietary folate equivalents (DFE). One microgram of DFE is equivalent to 1 mcg dietary folate, 0.6 mcg folic acid consumed with food, or 0.5 mcg supplemental folic acid on an empty stomach. Deficiency of folate is defined as concentration less than 7nmol/L to less than 10nmol/L for serum folate. Red blood cell (RBC) folate reflects folate status over months with levels less than 315 to 363 nmol/L suggesting deficiency.4
Reduced enzyme efficiency also has a part in influencing nutrient metabolism and disease risk as much as folate deficiency and excess intake. One of the enzymes is Methylenetetrahydrofolate reductase (MTHFR) that catalyses reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (5-MTHF). It is encoded by the gene MTHFR. There are two MTHFR gene polymorphisms with reduced enzyme efficiency:C677T and A1298C.4 The second key enzyme is Cytosolic serine hydroxyl methyl transferase (SHMT1) that converts serine and tetrahydrofolate to glycine and 5,10-methylenetetrahydrofolate respectively.4.
REVIEW OF META-ANALYSES
Two meta-analyses of Randomised Controlled Trials (RCTs) and a meta-analysis with 12 RCTs and 7 observational studies, evaluated the impact of FA supplementation, with or without other B vitamins, on cancer risk.4 Doses of FA ranged between 0.4 and 40 mg/day. Only one study used 5-methyltetrahydrofolate (5-MTHF), the metabolically active form of folate at a dose of 560 mcg/day.4 However, when that study was removed it did not change results. No significant effect of FA supplementation was found on total cancer risk in two of the analyses. One analysis reported a “borderline significant” 7% increase in overall cancer risk; however, the confidence interval (CI) included 1.2 Two analyses also found no significant association between FA supplementation and risk of colorectal, prostate, lung, breast, or haematological cancers4; however, one found a 24% increased risk of prostate cancer.2 One found no effect with less common types of cancer and cancers of unknown origin4; and another found a 53% lower risk of melanoma.4
In subgroup analysis, Qin (2013, cited by Renee4) found a 10% increased risk of cancer in studies where > 60% of participants were on lipid-lowering drugs and hypothesized that statin treatment interacting with homocysteine metabolism in the presence of FA supplementation may impact cancer risk.5 Wien (2012, cited by Renee4) reported a 21% increased risk of cancer with doses between 0.4 and 1 mg/day, but not with doses higher than 1 mg/day and a 19% increased risk in smokers.6
Additional analyses evaluating risk in specific cancer types found a significant 3% decrease in risk of renal cancer with 100-mcg FA supplementation in a dose-response analysis.4 When comparing highest with lowest intake from food fortification and supplements, two studies reported an inverse association and one study found no effect on risk of colorectal cancer.4
REVIEW OF META-ANALYSES
The actions of folate in cancer prevention appear to be modulated by both dosage and timing with respect to progression of carcinogenesis.
Folate deficiency has an inhibitory effect whereas folate supplementation may enhance the growth of existing colorectal neoplasms due to the function of folate in providing nucleotides for DNA synthesis.7
On the other hand, folate deficiency in normal colorectal mucosa puts it at a risk of being transformed into neoplasms, and optimal levels of folic acid supplementation suppress, whereas supraphysiologic supplemental doses (i.e., doses higher than the normal) enhance, the development of cancer in normal colorectal mucosa.7 This shows how time and dose plays a role in the association between cancer risk and folates.
CANCER TYPES AND FOLATE INTAKES
Folate intake has a protective effect for some cancers, little to no effect for others, and higher intake can increase risk. Renee Perioth et al. compared the highest to lowest intake of folate and found out the following: higher intake was associated with a decreased risk for squamous cell carcinoma of the head and neck (SCCHN); oral cavity and pharyngeal (OPC); all histological types of oesophageal; pancreatic; ovarian; and reduction in bladder cancers.4 They found out that there was no reduction in risk for lung cancer until they removed a study of all females due to variation in study outcomes between studies. Then, there was a 10% reduction in risk. The result is due to having a higher proportion of smokers as males. In summary, high intake of folate decreases the risk of cancer.
Recent studies have found that folate intake has little to no association with breast cancer, excluding those comparing higher alcohol consumption with lower folate intake. Chen et al. and Zhang et al. (2014, cited by Renee4) discovered a non-linear dose-effect association between dietary folate intake status and breast cancer risk. There was a significantly decreased breast cancer risk with dietary folate intake between 153 and 400 mcg compared with those of < 153 mcg, but there was not a statistically significant reduced risk with dietary folate intake > 400 mcg compared to < 153 mcg.8, Zhang et al. (2014, cited by Renee4) found a potential J-shape correlation between folate intake and breast cancer risk; daily folate intake of 200–320 mcg was associated with lower breast cancer risk, but the risk increased significantly with a daily folate intake > 400 mcg.9. Liu et al. (2014, cited by Renee4) found that a 220 mcg/day increment in dietary folate intake was not associated with breast cancer risk. There were varying incremental doses in several studies used to assess a dose-effect relationship.10
Gene polymorphisms associated with folate metabolic pathway may cause a variety of diseases. In a meta-analysis of 134 case-control studies, the MTHFR C677T polymorphism was significantly associated with increased tumour risk. Mutation of the 677 gene has been associated with increased risk of lung, hepatocellular, stomach, oesophageal, breast, brain and ovarian cancer in Asian population and breast cancer in Turkish population. MTHFR TT has also been associated with risk of thyroid cancer and increased risk of non-Hodgkin lymphoma in Caucasians.4
Meanwhile, MTHFR 677TT can protect against colorectal cancer, aggressive types of prostate cancer, and non-Hodgkin lymphoma in Asians. Similarly, in Asians, the genotype has been linked to a lower risk of oral cancer. High total and dietary folate intake were inversely related with colorectal cancer for the wild-type allele, whereas MTHFRTT showed a protective effect for colorectal with high total folate intake compared to low total folate intake.4
Now the second variant A1298C is also importantly related with increased risk for cervical cancer, globally and among Asians.4 Its homozygosity has also been associated with increased risk for myeloid leukaemia and non-Hodgkin lymphoma and decreased risk of liver cancer globally and among Asians.4
SHMT C1420T has been linked to a lower risk of colorectal cancer and overall cancer risk.4 Another research found no connection between SHMT and colorectal cancer, but a subgroup analysis revealed a substantial reduction in cancer risk when low folate intake was present in the presence of SHMT1 variation.
It has been established that a positive relationship exists between folate and cancer risk such that good folate status reduces cancer risk. However, if some factors are involved there might be a shift in this positive relationship.
- Martin Crook Vitamins, trace elements and metals In: Clinical Biochemistry and Metabolic Medicine (Hodder & Stoughton Ltd, 2012) p.230
- Wien TN, Pike E, Wisløff T, et al Cancer risk with folic acid supplements: a systematic review and meta-analysis BMJ Open 2012;2:e000653. doi: 10.1136/bmjopen-2011-000653
- Tomita Luciana Yuki. Folate and Cancer: Is There Any Association?. J. inborn errors metab. screen. [Internet]. 2016 [cited 2021 Apr 30] ; 4: e160016. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S2326-45942016000100402&lng=en. Epub May 30, 2019. https://doi.org/10.1177/2326409816661357.
- Pieroth R, Paver S, Day S, Lammersfeld C. Folate and Its Impact on Cancer Risk. Curr Nutr Rep. 2018 Sep;7(3):70-84. doi: 10.1007/s13668-018-0237-y. PMID: 30099693; PMCID: PMC6132377.
- Qin X, Cui Y, Shen L, Sun N, Zhang Y, Li J, Xu X, Wang B, Xu X, Huo Y, Wang X. Folic acid supplementation and cancer risk: a meta-analysis of randomized controlled trials. Int J Cancer. 2013 Sep 1;133(5):1033-41. doi: 10.1002/ijc.28038. Epub 2013 Feb 15. PMID: 23338728.
- Wien TN, Pike E, Wisløff T, Staff A, Smeland S, Klemp M. Cancer risk with folic acid supplements: a systematic review and meta-analysis. BMJ Open. 2012 Jan 12;2(1):e000653. doi: 10.1136/bmjopen-2011-000653. PMID: 22240654; PMCID: PMC3278486.
- Kim, Y.‐I. (2007), Folate and colorectal cancer: An evidence‐based critical review. Mol. Nutr. Food Res., 51: 267-292. https://doi.org/10.1002/mnfr.200600191
- Chen, P., Li, C., Li, X. et al. Higher dietary folate intake reduces the breast cancer risk: a systematic review and meta-analysis. Br J Cancer 110, 2327–2338 (2014). https://doi.org/10.1038/bjc.2014.155
- Zhang YF, Shi WW, Gao HF, Zhou L, Hou AJ, et al. (2014) Folate Intake and the Risk of Breast Cancer: A Dose-Response Meta-Analysis of Prospective Studies. PLOS ONE 9(6): e100044. https://doi.org/10.1371/journal.pone.0100044
- Liu M, Cui LH, Ma AG, Li N, Piao JM. Lack of effects of dietary folate intake on risk of breast cancer: an updated meta-analysis of prospective studies. Asian Pac J Cancer Prev. 2014;15(5):2323-8. doi: 10.7314/apjcp.2014.15.5.2323. PMID: 24716978.