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Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA
3To whom correspondence should be addressed. E-mail: nulrich{at}fhcrc.org.
ABSTRACT
The B vitamin folate is essential for one-carbon transfer reactions, including those related to the methylation of DNA or other substrates and nucleotide synthesis. Epidemiologic and experimental studies implicate low-folate intakes in elevated risk of colorectal neoplasia and suggest that biologic mechanisms underlying this relation include disturbances in DNA methylation patterns or adverse effects on DNA synthesis and repair. With the completion of the Human Genome Project, a vast amount of data on inherited genetic variability has become available. This genetic information can be used in studies of molecular epidemiology to provide information on multiple aspects of folate metabolism. First, studies linking polymorphisms in folate metabolism to an altered risk of cancer provide evidence for a causal link between this pathway and colorectal carcinogenesis. Second, studies on genetic characteristics can help clarify whether certain individuals may benefit from higher or lower intakes of folate or nutrients relevant to folate metabolism. Third, studies on genetic polymorphisms can generate hypotheses regarding possible biologic mechanisms that connect this pathway to carcinogenesis. Last, genetic variability in folate metabolism may predict survival after a cancer diagnosis, possibly via pharmacogenetic effects. To solve the puzzle of the folate-cancer relation, a transdisciplinary approach is needed that integrates knowledge from epidemiology, clinical studies, experimental nutrition, and mathematical modeling. This review illustrates knowledge that can be gained from molecular epidemiology in the context of nutrigenetics, and the questions that this approach can answer or raise.
KEY WORDS: • folate • polymorphism • genetics • colorectal cancer • MTHFR • TS • pharmacogenetics
Genetics in the "omics" age
Multiple "omics" technologies are increasingly used in nutrition research and provide new tools for understanding and deciphering biologic processes. Genetics plays a role in the "omics" age, because it can provide complementary information to other technologies. Inherited genetic characteristics, such as the presence of a variant allele at a polymorphic locus, represent permanent, life-long characteristics of an individual. Thus, measuring the presence of an inherited mutation that alters protein function or metabolism may be considered as the measurement of a long-term "exposure," potentially altering the molecular milieu both intracellularly and extracellularly. Further, many inexpensive assays are now available for characterizing an individual’s genetic makeup making the measurement of genetic characteristics amenable to high-throughput technologies with large sample sizes (1). Studies on colorectal cancer—a major public health problem in the developed world—and folate metabolism provide an excellent example of the use of genetics and nutrigenetics in molecular epidemiology.
Folate and carcinogenesis
The B-vitamin folate has been investigated in regard to colorectal carcinogenesis, because lower intakes of vegetables and fruit, sources of folate, are associated with increased risk of several types of cancer (2). Today, a large body of research, both epidemiologic and experimental, illustrates the importance of this specific nutrient in colorectal carcinogenesis (3,4). Low folate intakes, or biomarkers of low-folate status, have been implicated in increased risk of colorectal cancer in a number of studies (4). However, the underlying biologic mechanisms for these associations are still not well defined. Figure 1highlights one-carbon metabolism, including key enzymes involved, and major regulatory mechanisms. Folate functions as a donor of one-carbon units and is essential for methylation reactions (including DNA methylation), as well as for nucleotide synthesis, and thus DNA synthesis and repair (5,6). Accordingly, mechanisms linking folate to carcinogenesis include adverse effects on DNA methylation—both on global levels and at specific CpG sites in promoter regions—as well as on DNA damage and repair capacity.
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In addition to effects on DNA methylation and possible subsequent DNA damage, disturbances in one-carbon metabolism are known to cause DNA damage via effects on nucleotide synthesis. In the presence of folate deficiency, uracil is misincorporated into DNA. During the repair by uracil-glycosylase, DNA strand breaks can be induced, which can cause chromosomal damage and translocations (6). This degree of genomic instability is expected to enhance carcinogenic progression. A large number of experimental studies demonstrate that these effects of folate deficiency can be observed in vitro and in vivo (6). Some studies of apparently healthy individuals have shown correlations between a low vitamin B-12 and possibly folate status and the presence of micronuclei (an indicator of chromosomal DNA damage) among healthy individuals (16,17). Further, among individuals with high DNA damage at the outset, supplementation with folic acid and vitamin B-12 was successful in reducing the number of micronuclei (16).
Genetics and nutrigenetics of folate metabolism
With the completion of the Human Genome Project, a vast amount of data on inherited genetic variability has become available. This genetic information can be used in studies of molecular epidemiology to provide information on multiple aspects of folate metabolism. First, studies linking polymorphisms in folate metabolism to an altered risk of cancer provide evidence for a causal link between this pathway and colorectal carcinogenesis. This is critical because high dietary intakes of folate may also correlate with other nutritional factors or health behaviors, resulting in confounding. However, genetic characteristics usually follow the rules of "Mendelian randomization" and thus a priori no relation between genotypes and dietary intakes or health behaviors is expected (18). Second, studies on genetic characteristics can help clarify whether certain individuals may benefit from higher or lower intakes of folate or nutrients relevant to folate metabolism. Third, studies on genetic polymorphisms can assist in elucidating biologic mechanisms that link this pathway to carcinogenesis. Last, genetic variability in folate metabolism may predict survival after a cancer diagnosis, possibly via pharmacogenetic effects.
Within the folate pathway, polymorphisms with a functional impact on protein function have been described in most of the key enzymes [reviewed in (19)]. Most of the molecular epidemiologic studies to date have focused on these specific "candidate polymorphisms." However, an approach that investigates one individual candidate polymorphism at a time is limited in that it does not account for other genetic variants within the same biologic pathway or for other genetic polymorphisms within the same gene. Future studies should include comprehensive investigations covering genetic variability in a multitude of biologically interrelated proteins, with study sizes that are sufficient to investigate gene-gene and gene-environment interactions. Appropriate statistical tools for this pathway-based approach are necessary (20), and care needs to be taken that study designs follow epidemiologic principles (21). A candidate polymorphism approach also does not account for additional genetic variation within the same gene or in adjacent genomic regions, a limitation that can lead to associations with a particular polymorphisms that may be in linkage disequilibrium with a true causal variant. Resources such as the HapMap Project and dBSNP databases will enable researchers to address genetic variability in larger genetic regions (22).
Nevertheless, the "candidate polymorphism" studies undertaken to date have provided us with intriguing information about the relation between folate and disease risk. To date, polymorphisms in 5,10-methylene-tetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), methionine synthase, methionine synthase reductase, serine-hydroxymethyltransferase, cystathionine ß-synthase, methylene-tetrahydrofolate dehydrogenase, and glutamate carboxypeptidase have been investigated in relation to the risk of colorectal cancer or polyps; however, several of these have only been investigated in single studies. A comprehensive review of this literature is beyond the scope of this paper, and readers are referred elsewhere (21,23,24). Examples given below illustrate the knowledge that can be gained from molecular epidemiology, and the questions that this approach can answer or raise.
Are gene-diet interactions meaningful?
Genetic factors clearly play a role in carcinogenesis, as evidenced by an increased risk of cancer among a patient’s family members or offspring. However, migrant studies provide unequivocal evidence that environmental factors are critical in defining cancer risk, because cancer risk assimilates within few generations to the risk of the host country (25,26). In the presence of a certain exposure, e.g., smoking, only a subset of individuals will develop cancer, arguing for interactions with other factors, including the genetic background of the host. On the molecular level, a rationale for investigating interactions is given by the paradigm that pathways or biologic systems are generally robust. Perturbations at any point within the system are unlikely to cause major harm, and thus, one may expect to see an adverse impact of genetic factors largely if the system is "under stress." Hartwell (27) has described how the joint occurrence of 2 mutations in separate genes can remove some of the "robustness" within a pathway, arguing for the relevance of gene–gene interactions. Similarly, one may expect that with a lower availability of substrate for biochemical reactions, genetic changes in enzyme function become more pronounced. In the context of folate metabolism, one can observe this relation for MTHFR. Most studies to date indicate that the variant MTHFR genotype 677TT (which encodes a thermolabile form of the enzyme with reduced in vitro function) is related to biomarkers, such as homocysteine concentrations or global DNA methylation particularly in the presence of a diet low in folate (28–31). Thus, the investigation of gene–diet interactions is not only useful, but essential to gain a full understanding of the impact of genetic variation on health outcomes.
Intriguingly, a modestly reduced risk of colorectal neoplasia has been observed for the MTHFR 677TT genotype (21,32), with quite consistent patterns of gene–diet interactions. Studies of both adenomatous polyps, precursors of colorectal cancer, or carcinoma show that a variant MTHFR 677TT genotype is associated with a decreased risk largely in the presence of higher intakes of folate, vitamins B-6, B-12, and possibly B-2 or lower alcohol intake; however, the risk of adenoma can be increased when there is lower intake of nutrients involved in one-carbon metabolism (33–39). Thus the nutritional status of the population under study may determine which section of this interaction—decrease or increase, depending on the nutritional level of the reference group—is observed. Whereas several business entities are already using these limited data for marketing of genetic testing and "genetically targeted" nutrient supplementation (40), we need to remind ourselves that we are just at the beginning of explorations into the interactions between genetics and dietary factors, and the knowledge base is simply insufficient at this point to derive public health recommendations.
Molecular epidemiology and biologic mechanisms
Although molecular epidemiology does not investigate biologic mechanisms per se, findings from epidemiologic studies can provide hypotheses regarding those mechanisms. The inverse associations observed with genetically reduced MTHFR activity (e.g., a 677TT genotype) were initially attributed to a greater diversion of its substrate, 5,10-methyleneTHF, toward pyrimidine synthesis via the enzyme TS (41). A recent study by Quinlivan and colleagues (42) provides some evidence for this effect of MTHFR 677TT on thymidine synthesis. However, studies of polymorphisms in TS may point also toward an alternative explanation. The 5'-UTR of the TS gene contains polymorphic 28-bp tandem repeats; the triple repeat results in an 
2- to 4-fold greater gene expression than the double repeat (43). Unexpectedly, individuals with the TS 2R/2R genotype are not at an increased risk of colorectal cancer or its precursors, yet experience a somewhat decreased risk (44–46). Furthermore, individuals with the 3R/3R genotype (=higher expression) appear more susceptible to colorectal adenoma in the presence of low-folate or high alcohol intakes, whereas no such relationships were observed for individuals with the 2R/2R genotypes (44,46). Lastly, a study of colorectal polyps that investigated the MTHFR C677T polymorphism concurrently with the TS variant, reported that individuals who had low MTHFR activity (677TT) and low TS expression (TSER 2R/2R) were unexpectedly the group at lowest risk of colorectal adenoma (44). Similar results were also observed in a colon cancer study of >1500 cases and >1900 population controls (Ulrich et al., unpublished results).
These findings can generally not be reconciled with the hypothesis that a greater diversion of 5,10-methyleneTHF toward thymidine synthesis is critical for a reduction of colorectal cancer risk. Although these findings are not entirely consistent between populations, possibly because of insufficient sample sizes in some investigations, they suggest that the availability of 5,10-methyleneTHF for a third pathway, purine synthesis, may be a relevant mechanism linking folate to colorectal carcinogenesis (Fig. 1). In fact, depurination is the most common form of spontaneous DNA damage (48,49). Although endonucleases efficiently repair this damage, abasic sites exist in cellular DNA, with steady-state levels of about 5–10,000 lesions per cell (49). Conceivably, purine synthesis may be the most protected pathway with respect to folate metabolism and colon carcinogenesis. Research with in vivo carbon tracers provides initial support for a relation between MTHFR genotypes and purine synthesis (42); however, this study did not investigate genotypes of TS. Further epidemiologic and experimental studies are needed to confirm or disprove this hypothesis.
Beyond primary cancer prevention: secondary prevention and pharmacogenetics of folate metabolism
Whereas a low-folate status may enhance carcinogenesis, the relation may be complex, in that concerns have been raised that an excessive intake can do harm (50). With folic-acid fortification of food (51), folic acid intake in subsets of the population using vitamin supplements can exceed recommendations. In animal models, folate supplementation is an effective chemopreventive agent if given prior to the establishment of early lesions (e.g., aberrant crypt foci), and this activity has been attributed to adequate supplies for methylation reactions and nucleotide synthesis. However, once a preneoplastic lesion is present, folate enhances tumor growth, probably because of the dependence of rapidly dividing tissues on folate for DNA synthesis. These relations have been initially described in animal experiments (52,53), but there is now some evidence from a randomized controlled trial, demonstrating that folic acid supplementation among patients with resected adenoma may enhance the recurrence of multiple or larger adenomas (54). Preliminary results suggest that prediagnostic use of folic acid supplements is associated with shorter survival, and that genetic factors may also play a role (Ulrich et al., unpublished results). Nutrigenetics may also be relevant in this setting, in that individuals with specific genotypes may not benefit from high intakes of folic acid. For example, high intakes of folate may enhance adenoma risk among individuals with the TS 2R/2R genotype (44). Thus, the role of folic acid in cancer survivorship and the interplay with genetic factors is a critical question requiring further research.
The role of folate in tumor growth is also exemplified by the use of folate antagonists in cancer treatment. Both antifolates (e.g., methotrexate), and TS inhibitors (e.g., 5-fluorouracil) target folate metabolism. Polymorphisms in key enzymes of folate metabolism can predict treatment response to these chemotherapeutics, although most studies have been too small to yield definite conclusions [for reviews see (19,55)]. The question of variable intakes of one-carbon nutrients, or use of supplements, their interaction with genetic characteristics, and possible effects on treatment outcomes, has not yet been addressed. This is a relevant concern because of the increasing use of nutritional supplements in the population, especially among cancer patients.
Summary
To solve the puzzle of the folate-cancer relation, a much better understanding of the combined effects of multiple genetic variants under different nutritional conditions on specific biomarkers is needed. Most fruitful to this undertaking will be a transdisciplinary approach that includes epidemiology, clinical studies, experimental nutrition, and potentially mathematical modeling. Epidemiologic studies should attempt to measure relevant biomarkers (e.g., DNA methylation) to substantiate hypotheses about the involvement of specific biologic mechanisms. Unfortunately, only a limited set of biomarkers is currently suitable for the inclusion in epidemiologic studies, both because of cost and accessibility to biologically relevant samples. Further, the presence of a tumor can alter some biomarkers, restricting their use to prospectively collected specimens. Studies in experimental nutrition, both in humans and animal models, continue to be indispensable for providing critical information about mechanisms of action of dietary components. The development of a mathematical model of the biochemical characteristics of folate-mediated one-carbon metabolism, including its links to DNA methylation and nucleotide synthesis, will permit simulations of multiple genotypes and nutritional input parameters. Such a model is currently under development, and initial results have been published (56). The ease of manipulation within a mathematical model will render it a useful tool to the research community by substantiating findings from epidemiologic studies and by suggesting specific research questions that can be addressed through laboratory investigations.
ACKNOWLEDGMENTS
I would like to thank Clayton Hibbert for assistance with the graphics.
FOOTNOTES
1 Presented as part of the symposium "Nutritional ‘Omics’ Technologies for Elucidating the Roles of Bioactive Food Components in Colon Cancer Prevention" given at the 2005 Experimental Biology meeting on April 5, 2005, San Diego, CA. The symposium was sponsored by the American Society for Nutritional Sciences and in part by the Diet and Cancer and Dietary Bioactive Food Components Research Interest Sections. The proceedings are published as a supplement to The Journal of Nutrition. This supplement is the responsibility of the Guest Editors to whom the Editor of The Journal of Nutrition has delegated supervision of both technical conformity to the published regulations of The Journal of Nutrition and general oversight of the scientific merit of each article. The opinions expressed in this publication are those of the authors and are not attributable to the sponsors or the publisher, editor, or editorial board of The Journal of Nutrition. The guest editors for the supplement publication are Cindy D. Davis, National Cancer Institute, National Institutes of Health, and Norman Hord, Department of Food Science and Human Nutrition, Michigan State University. 
2 This work has been supported by grants from the National Institute of Health, CA59045 (PI Potter) and CA105437 (PI Ulrich).
4 Abbreviations used: MTHFR, methylene-tetrahydrofolate reductase; SAM, S-adenosylmethionine; THF, tetrahydrofolate; TS, thymidylate synthase.
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Y. N. Martin, J. E. Olson, J. N. Ingle, R. A. Vierkant, Z. S. Fredericksen, V. S. Pankratz, Y. Wu, D. J. Schaid, T. A. Sellers, and R. M. Weinshilboum Methylenetetrahydrofolate Reductase Haplotype Tag Single-Nucleotide Polymorphisms and Risk of Breast Cancer. Cancer Epidemiol. Biomarkers Prev., November 1, 2006; 15(11): 2322 - 2324. [Full Text] [PDF]
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C. M. Ulrich, H. F. Nijhout, and M. C. Reed Mathematical modeling: epidemiology meets systems biology. Cancer Epidemiol. Biomarkers Prev., May 1, 2006; 15(5): 827 - 829. [Full Text] [PDF]
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