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Human Nutrition Unit, University of Sheffield, UK
4To whom correspondence should be addressed. E-mail: h.j.powers{at}sheffield.ac.uk.
ABSTRACT
Epidemiological studies have linked low folate intake with an increased risk of epithelial cancers, including colorectal cancer and cervical cancer. Riboflavin has received much less attention, but there is increasing interest in the well-established role that flavins play in folate metabolism and the possible synergy of a protective effect between these 2 vitamins. Folate plays a key role in DNA synthesis, repair, and methylation, and this forms the basis of mechanistic explanations for a putative role for folate in cancer prevention. The role of folate in these processes may be modulated by genotype for the common C677T thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), homozygosity for which is associated with lower enzyme activity, lower plasma and red blood cell folate, and elevated plasma homocysteine. Riboflavin, as FAD, is a cofactor for MTHFR and there is evidently some interaction among riboflavin status, folate status, and genotype in determining plasma homocysteine, a functional marker of folate status. The MTHFR C677T polymorphism appears to interact with folate and riboflavin in modulating cancer risk in a manner that varies according to cancer site. Most evidence points to a protective effect of this polymorphism for risk of colorectal cancer, but the effect on cervical cancer risk is not clear. The effect of this polymorphism on cancer risk seems to be further modulated by other factors, including alcohol and, in the case of cervical cancer, infection with the human papilloma virus. An additional factor determining the effect of diet and genotype interactions on cancer risk may be the stage of cancer development.
KEY WORDS: • riboflavin • folate • MTHFR C677T • cancer
A significant body of research suggests that a diet rich in fruit and vegetables may protect against cancer at various sites. Nutrients and nonnutrient plant compounds have been examined as putative factors in this protective process; among these compounds folate has received a certain amount of attention, especially with respect to epithelial cancers. Folate is an attractive candidate in this context, because some epidemiological studies have supported a protective role, and there are also plausible explanatory mechanisms. Riboflavin has received much less attention, but interest is increasing in the well-established role that flavins play in folate metabolism and the possible synergy of a protective effect between these two vitamins, which may be important in the context of Western diets, in which low intakes of both folate and riboflavin are reported in some groups.
Folate and DNA stability
Folate, as 5,10-methylene tetrahydrofolate, is an essential 1-C donor in the synthesis of DNA and, as 5-methyl tetrahydrofolate, in the methylation of DNA (Fig. 1). Methylation occurs on cytosine residues in cytosine-guanine sequences (CpGs),5 and the methylation profile of DNA is evidently important for carcinogenesis, although the reasons for this are not fully understood. Hypomethylation of DNA is an early feature of carcinogenesis (1,2). Feinberg and Vogelstein (3) were among the first to report DNA hypomethylation in colorectal tumor tissue. Although folate is clearly important to DNA methylation, the evidence that dietary folate deprivation alone is sufficient to cause hypomethylation in vivo has not been unequivocally established, and any effects may indeed be tissue specific. Rats fed a methyl-deficient diet showed evidence of global DNA hypomethylation in the liver (4), whereas folate deficiency in rats has been associated with hypomethylation in the TP53 gene in tissue from the liver and colon. Other studies have reported that folate deficiency in rats does not induce global hypomethylation or hypomethylation of c-myc in liver or colonic TP53 (5,6). Notably, some evidence has emerged to suggest that folate deficiency may induce hypomethylation only at specific sites on cancer-relevant genes (1). Evidence is also emerging that folate deficiency may lead to hypermethylation of sites within the promoter regions for certain tumor suppressor genes, leading to gene silencing (7,8). Conversely, increasing folate intake can influence DNA methylation under certain circumstances. A recent study among patients with colorectal adenoma demonstrated that a supplement of 400 µg folic acid for 10 wk elicited a significant increase in global DNA methylation in leukocytes and a nonsignificant increase in colonic mucosa (9).
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Folate, riboflavin, and genotype
The role of folate in these processes may be modulated by genotype for the common C677T thermolabile variant of methylene tetrahydrofolate reductase (MTHFR). This enzyme converts 5,10-methylene tetrahydrofolate to 5-methyl tetrahydrofolate, which is the methyl donor for the conversion of homocysteine to methionine and key to the provision of S-adenosyl methionine for DNA (and other substrate) methylation. Individuals carrying the TT variant (homozygous) show lower enzyme activity, lower plasma folate, and elevated plasma homocysteine (19,20). In addition, homozygosity is associated with a change in the profile of RBC folates, with an increased proportion being in the formyl tetrahydrofolate polyglutamate form (21). The activity of MTHFR seems therefore to be a determinant of the availability of folate for DNA synthesis or methylation. Riboflavin, as FAD, is a cofactor for MTHFR, and there is evidently some interaction between riboflavin status, folate status, and genotype in determining plasma homocysteine, a functional marker of folate status (22,23,24). A study of the MTHFR expressed in Escherichia coli suggests that the TT variant of the enzyme may be less tightly bound to its FAD cofactor, whereas 5-methyl tetrahydrofolate may to some extent protect the enzyme against this effect (25).
Polymorphisms in the MTHFR gene may modulate effects of folate on susceptibility to cancer risk at certain sites, although there is a great deal of uncertainty in this area. Interestingly, polymorphisms in MTHFR may interact with folate status to influence genomic methylation. A recent study by Friso et al. (26) reports that subjects with low folate status and carrying the TT variant of the MTHFR C677T polymorphism had relative hypomethylation of DNA extracted from whole blood compared with homozygous wild types, an effect that was mitigated by high folate status. Other studies also observed DNA hypomethylation in association with the C-to-T polymorphism in MTHFR (27,28). Furthermore, increased leukocyte global DNA methylation in response to folate supplementation may be modulated by homozygosity for the C677T MTHFR polymorphism (29). However, not all groups report an effect of MTHFR polymorphism on DNA methylation (30), and these inconsistencies may be related to the folate status and the frequency of the TT variant in the study population.
Folate, riboflavin, genotype, and colorectal cancer
Evidence from human studies for a role for folate in determining cancer risk is equivocal. Much of the work in this area has concerned colorectal cancer, for which there is evidence from epidemiological studies for a protective role for folate. A number of case-control studies have demonstrated an inverse association between folate intake and risk of colorectal cancer (31–33), with an average reduction of about 30% for the highest versus the lowest folate intakes. Interestingly, alcohol intake may mitigate protective effects of folate (34). Results of studies examining associations between biochemical measures of folate status and risk of colorectal adenoma or cancer are inconsistent. Perhaps of particular relevance is the observation that folate concentration in the healthy mucosa of patients with colorectal adenoma was lower than in control subjects even though circulating folate concentrations did not differ between these two groups (35). However, others reported no difference in folate concentration in colonocytes from normal tissue between patients with colorectal adenoma and healthy controls (36). It would be helpful to establish whether folate concentrations in colonic mucosa are sensitive to changes in folate intakes.
Very few folate intervention trials have been carried out, and those that have been reported have been small studies focusing on patient groups with increased risk of colorectal cancer. Furthermore, outcomes of interest have in almost all cases been intermediate disease endpoints, such as DNA methylation, mucosal cell proliferation, or DNA strand breakage. Results are inconsistent. Biasco et al. (37) showed a reduction in rectal cell proliferation in response to 3 mo of folic acid supplementation in patients with ulcerative colitis, whereas a study in Greece failed to show a significant effect of folic acid supplementation for 12 mo on adenoma recurrence (38). On the other hand, Cravo et al. (39) showed an increase in rectal mucosa DNA methylation after high-dose folic acid treatment for 6 mo. Clearly, additional folate intervention trials in humans are needed, and the results of 3 large-scale intervention trials in the United States are eagerly awaited. However, in view of the complexity and expense of such trials, there remains an interest in the development of biomarkers of cancer risk that are both responsive to exposure to the nutrient of interest while also reflecting cancer risk.
In light of those studies suggesting a modulating effect of MTHFR C677T genotype in determining functional folate status, it is reasonable to consider the importance of this polymorphism in determining cancer risk. In their 2004 review of this subject, Sharp and Little (40) showed that the majority of studies suggest a protective role for this polymorphism. A further complicating factor that should be factored into new studies is the possible role of riboflavin. Although FAD acts as a cofactor for MTHFR and riboflavin intake influences functional folate status, few studies have examined the possible contribution that riboflavin might make to protection against cancer. Of interest therefore are results from 2 case-control studies that suggest a protective effect of an interaction between riboflavin and the TT variant of MTHFR C677T to reduce the risk of colorectal cancer (41,42) (Fig. 2). These observations are supported by data showing an interaction between riboflavin and folate and this polymorphism in the MTHFR gene to determine genomic stability in cultured human lymphocytes (43).
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Cervical cancer has the second-highest incidence of cancers in women, after breast cancer. The incidence is far higher in developing countries than in developed countries, with about 83% of cases occurring in developing countries. Recent global statistics point to age-standardized incidence rates in developed countries of <14.5/100,000, compared with values as high as 42.7/100,000 in developing countries (44). Cervical lesions are classified according to the degree of cellular abnormality. The lowest grade of abnormality is cervical intraepithelial neoplasia 1 (CIN1), and CIN2 and CIN3 describe progressive epithelial dysplasia leading to invasive cancer. Preinvasive lesions have also been classified in terms of low-grade and high-grade squamous intraepithelial lesions. There is a high rate of regression of early-stage dysplasia, reported variously as being between 30 and 62%; regression rates fall with increasing dysplasia.
The key factor in cervical cancer causation is infection with human papillomavirus (HPV). There are >100 strains of this virus, 
40 of which can infect the genital tract. HPV strains have been divided into those that are considered low risk and those considered to be high risk for the development of cervical cancer. Although there is not universal agreement on the precise classification of all HPV strains, a recent large international study listed 15 HPV types that should be considered to fall in the high-risk category (45). HPV DNA is more common in cervical cells of women with cervical cancer than in healthy control subjects (46), and antibodies to high-risk HPV proteins are more common in the serum of cervical cancer patients. Epidemiological evidence shows convincingly that HPV infection is a necessary cause of cervical cancer (47). However, HPV infection is usually transient, and only a small proportion of women who test positive for high-risk HPV infection go on to develop cervical cancer. HPV infection may be necessary but is not sufficient to cause cervical cancer. Nutritional factors may affect the persistence of HPV infection and thereby influence progression of early precancerous lesions to invasive cancer.
Epidemiological studies support a role for diets rich in fruits and vegetables as protecting against cervical cancer (48–50). Folates have been considered as plausible protective factors in such diets, and a number of case-control studies, prospective cohort studies, and small intervention trials were carried out to examine this possibility. Nine case-control studies examined the association between folate intake and preinvasive cervical lesions or cervical cancer, but the results are not consistent. Of these, 4 suggested a protective effect. VanEenwyk et al. (51), who performed a hospital-based study, and Ziegler et al. (52), who conducted a population-based study, suggested a nonsignificant protective effect. Liu et al. (53) and Kwasniewska et al. (54) suggested a protective effect of higher folate intakes, but in the other case-control studies a protective effect for folate was not evident (55–59). Furthermore, only 4 (53,56–58) of the 9 studies corrected for HPV, which limits the interpretation of results. Some case-control studies used plasma folate as an exposure of interest, of which 2 studies suggested a protective effect against cervical cancer, although not significant, whereas a third, which was hospital-based, did not (60). Other case-control studies used RBC folate as an exposure, which is a more robust indicator of long-term folate status, and these generally supported a protective effect of folate against precancerous cervical lesions (57,59,61–63), that by VanEenwyk et al. (64) significantly so. In addition to the use of folate in blood as an exposure to dietary sources of this vitamin, some studies examined the relation between plasma homocysteine and risk of cervical cancer or precancerous lesions. The concentration of plasma homocysteine is considered to be a functional marker of intracellular folate availability (the two variables showing an inverse relation) and may therefore be a more useful measure than circulating concentrations of folate. Weinstein et al. (61) and Ziegler et al. (65) were able to show a significant increase in risk of invasive cervical cancer for women with elevated plasma homocysteine in population-based case-control studies, and Thomson et al. (66) showed a similar effect for noninvasive lesions. Despite some encouraging results from these case-control studies, randomized controlled trials have not generated convincing evidence for a protective effect of folate. Four randomized controlled trials were conducted (67–70), only one of which demonstrated a protective effect of folic acid supplements. However, these studies were generally small and, notably, did not correct for HPV infection, so results need to be interpreted cautiously.
Folate and HPV infection
The persistence of HPV infection is reported to be a key factor determining risk of developing intraepithelial cervical lesions and cervical cancer (71); therefore, interventions that control viral proliferation should be important to cancer prevention. A few groups examined whether specific nutrient intake might influence this. Giuliano et al. (72) conducted a nested case-control study of dietary intake and HPV persistence over 12 mo in a large cohort of Brazilian women. Unfortunately, a restricted FFQ was used to estimate dietary intake, and the focus of interest was clearly on carotenoids, although other nutrients were included in the final analysis. Increased intake of ß-cryptoxanthin, lutein plus zeaxanthin, and vitamin C were inversely associated with persistent HPV infection. The authors suggested that carotenoids and vitamin C might limit HPV infection through antioxidant activity, which in other models modulated response to viral infection (73). This is plausible because antioxidant activity was shown to reduce HPV transcription in the cervical cell line HeLa (74), and HPV-16 expression was shown to be modulated by redox status in vitro (75). Interestingly, in the Giuliano study average intakes of folates were only about 50% of the RDA and of vitamin B-6 were only about 30% of the RDA, in contrast to vitamin A intakes, which were generally adequate with a reasonably wide range. This suggests that either the FFQ used could not capture these nutrients adequately or that this population did have low intakes of folate and vitamin B-6. This is relevant because folate and vitamin B-6 are important in the methylation cycle and may influence HPV persistence through viral DNA methylation. Rosl et al. (76) demonstrated that HPV-18 DNA methylation downregulated transcription. Viral DNA methylation is evidently a determinant of viral transcriptional activity and therefore of viral proliferation. Riboflavin may modulate this effect through its cofactor role for MTHFR. Sedjo et al. (77) examined the relation between HPV persistence and nutrients involved in methylation, including folate, vitamin B-12, vitamin B-6, and methionine. In a large prospective cohort study, using a validated FFQ and measurements of plasma concentrations of the nutrients of interest, higher plasma vitamin B-12 was inversely associated with HPV persistence over 9 mo. Notably, a recent prospective cohort study carried out over 24 mo showed a significant protective effect of plasma folate > 2.4 nmol on risk of becoming high-risk HPV positive and of HPV persistence (78). The effect was still evident after correcting for other micronutrients. The relevance of folate to HPV persistence is also evident from the elegant studies of Pillai et al. (79), in which the expression of folate receptors in cervical cells decreased with increasing severity of cervical dysplasia. Expression of folate receptors correlates positively with heterogeneous ribonucleoprotein, which can inhibit HVP-16 proliferation in vitro.
The influence of C677T MTHFR genotype
The influence of C677T MTHFR genotype on cervical cancer risk is not at all clear. A few studies examined the possible association between cervical cancer and genotype for this mutation, but results are conflicting. Zoodsma et al. (80) recently reported a study of genotype for C677T MTHFR in CIN and cervical cancer patients and healthy control subjects. They showed a reduction in risk of cervical cancer in women who were heterozygous or homozygous for the C-to-T mutation. In contrast, 2 other smaller studies suggested that MTHFR C677T was a risk factor for CIN (81,82). Henao et al. (83) also reported a protective effect of MTHFR C677T for CIN2 and CIN3 in a population with adequate folate intake. Gerhard et al. (84) failed to show an association between MTHFR C677T and either cervical cancer or infection with high-risk HPV, and this was also true for the study by Lambropoulos et al. (85). Thus, although there may be an interaction between this common polymorphism in a folate metabolizing gene and risk of cervical cancer, there is currently no consensus of results.
In light of the studies previously conducted and, in particular, the lack of controlling for HPV infection and MTHFR C677T genotype, we have initiated a placebo-controlled double-blind intervention trial to explore the effects of folic acid with riboflavin on the regression of early precancerous cervical lesions. Follen et al. (86) published a frank commentary on why most randomized phase II cervical cancer chemoprevention trials are uninformative. Although the focus of this commentary was not nutritional intervention, the points raised are relevant. Briefly, this group identified key factors to consider in designing phase II trials of cervical cancer: the natural history of cervical cancer (in terms of regression rates of neoplasia), an important determinant of sample size; dose and duration of intervention to elicit the desired response; and consistency in classification of disease status at entry and as outcome.
Women are currently being recruited to the intervention trial on the basis of a colposcopy-directed biopsy diagnosis of CIN1 and an oncogenic HPV infection, and C677T genotype is determined for all volunteers. The patients are randomly assigned to receive either 1.2 mg folic acid and 5 mg riboflavin or placebo for 12 mo. At baseline and postintervention, samples of cervical cells are collected for the measurement of tissue folate status and DNA stability; cervical swabs are collected to provide cells for HPV testing and for the measurement of gene-specific methylation; and blood samples are collected for the measurement of systemic folate and riboflavin status and for MTHFR genotyping. The primary outcome is biopsy confirmation of regression of CIN; secondary outcome measures include markers of DNA stability (uracil misincorporation, strand breakage) and gene-specific methylation.
Gene-specific methylation
Variation in promoter methylation for individual genes was reported for cancers at different sites. There is a small literature describing methylation status of various genes in DNA isolated from cervical cells. Narayan et al. (87) found gene promoter hypermethylation in >80% of cases of cervical cancer, with the 4 most frequently methylated genes being CDH1, DAPK, RARB, and HIC1, with an increased hypermethylation in more advanced stages of cancer. Virmani et al. (88) reported a similar increase in DNA methylation with increasing severity of pathological change. Interestingly, there was a different methylation pattern of different genes according to pathology; thus, methylation of RARB and GSTP1 appeared to be an early event, in contrast with CDKN2A and MGMT, which occurred later in the development of invasive cervical cancer. Taken together, these and other studies in this area (89,90) suggest that hypermethylation of certain tumor suppressor genes may be related to the development of cervical cancer. Work from Kang et al. (91) indicated that there may be an interaction between polymorphisms in MTHFR and CpG island methylation status of cancer-related genes. Specifically, subjects carrying one or more T allele for the MTHFR C-to-T polymorphism showed a reduced level of aberrant hypermethylation in the promoter region of methyl guanine DNA methyl transferase, a DNA repair gene, suggesting a protective effect of the C-to-T polymorphism. Further investigation is warranted to determine any role for folate in influencing the methylation status of key genes. A clearer understanding of hypermethylation of genes in cervical neoplasia and cancer may help in the development of prognostic biomarkers and in the identification of gene targets for treatment.
Conclusion
Epidemiological studies point to a protective effect of folate against cancers, particularly those of epithelial origin, although there is currently little support from intervention trials. The MTHFR C7677T mutation appears to interact with folate in determining cancer risk, and there may be further interaction with riboflavin status. The effect of this mutation on cancer risk may be site specific in that individuals carrying the TT variant appear to be protected against colorectal cancer, but the situation with respect to cervical cancer is much less clear at present. Evidence for a protective effect of folate against cervical cancer is currently weak, but this may be partly due to a failure to consider the role of HPV infection as a key risk factor. Folate may modulate HPV persistence and thereby influence cancer risk.
FOOTNOTES
1 Published in a supplement to The Journal of Nutrition. Presented as part of the International Research Conference on Food, Nutrition, and Cancer held in Washington, DC, July 14–15, 2005. This conference was organized by the American Institute for Cancer Research and the World Cancer Research Fund International and sponsored by (in alphabetical order) California Avocado Commission; California Walnut Commission; Campbell Soup Company; The Cranberry Institute; Danisco USA, Inc.; The Hormel Institute; National Fisheries Institute; The Solae Company; and United Soybean Board. Guest editors for this symposium were Vay Liang W. Go, Ritva R. Butrum, and Helen A. Norman. Guest Editor Disclosure: R. R. Butrum and H. Norman are employed by conference sponsor American Institute for Cancer Research; V.L.W. Go, no relationships to disclose. 
2 Author Disclosure: No relationships to disclose.
3 Some of the work referred to in this manuscript was supported by research grants from the Food Standards Agency (N12004/6) and the World Cancer Research Fund International (2003/51).
5 Abbreviations used: CIN, cervical intraepithelial neoplasia; CpG, cytosine-guanine sequence; HPV, human papillomavirus; MS, methionine synthase; MTHFR, methylene tetrahydrofolate reductase.
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