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4 Human Nutrition Research Centre, School of Clinical Medical Sciences and 5 Human Nutrition Research Centre, Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
* To whom correspondence should be addressed. E-mail: john.mathers{at}ncl.ac.uk.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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Despite its well-recognized limitations, birth weight has been used widely as a summary measure of the normality of intrauterine growth. Although the impact of intrauterine growth trajectory on risk of hypertension, cardiovascular disease, and type 2 diabetes has been described extensively, the impact on cancer risk is much less understood. There is evidence that higher birth weight may increase the overall risk of cancer in adulthood for both men and women (2). However, for women this increased risk appears to be restricted to cancers (notably breast cancer) in those aged under 50 y, and there is some support for the hypothesis that higher birth weight may be associated with lower risk of endometrial cancer (2). A recent review of effects of early-life exposures on breast cancer risk has confirmed the greater risk of premenopausal breast cancer in women with relatively greater birth weights (3). If the relation between birth weight and adult obesity is U-shaped [as suggested by the study of Leong et al. (4)], then those at opposite ends of the birth weight range may share an increased risk of cancer in later life because obesity is a significant risk factor for cancers at many sites (5). The role of genetic polymorphisms, alone or in interactions with nutrition and other intrauterine exposures, in determining birth weight is poorly understood. For most major cancers, age is a significant carcinogen (6), which suggests that the effectiveness of genomic defenses declines with age, thus allowing the accumulation of DNA damage that is fundamental to tumorigenesis.
Diet-gene interactions and cancer risk
Genome-wide single-nucleotide polymorphism (SNP)6 studies require very large cohorts, and such large groups are difficult to incorporate into any study where a nutrient-gene interaction is thought to be a key factor. The alternative to genome-wide searches for association of SNPs with disease susceptibility is to adopt a hypothesis-based approach focused on specific nutrients or metabolic pathways. The advantages of such an approach are 3-fold. First, the framework provided by the hypothesis gives a focus to particular metabolic pathways and thus to specific target genes for SNP analysis. Second, it is possible to examine nutrient-gene interactions. Third, combining nutritional and mechanistic data with the epidemiologic and genetic information strengthens the evidence for the proposed associations.
Such hypothesis-driven SNP studies often follow naturally from epidemiologic observations on nutrient- or food-based effects. For example, the enzyme manganese superoxide dismutase (MnSOD) plays a key role in antioxidant defense. It is synthesized in the cytoplasm and translocated to the mitochondrial matrix, where the active enzyme functions as a homotetramer. An SNP at codon 16 in the mitochondrial targeting sequence encodes for a valine (Val) or alanine (Ala) in the protein. This amino acid change may affect the secondary structure of the protein and, therefore, the efficiency of transport into the mitochondrion, with more efficient transport with the Ala form (7). This polymorphism is quite common with allelic frequencies for Ala ranging from 
12% (in Japanese) (8) up to 55% (in Caucasians) (9). Risk of both breast (9) and prostate cancer (10) appears to be modified by this polymorphism. In a recently reported analysis of prospective data from the Physicians' Health Study, there was evidence that those homozygous for the Ala form of the MnSOD SNP had a slightly (but not significantly) higher risk of total and aggressive prostate cancer [defined as stage C or D high-grade tumor (Gleason score 7–10) or prostate cancer death] (11). However, prediagnostic concentrations of several plasma antioxidants (viz. carotenoids, vitamin E, retinol, and selenium) had been determined, and antioxidant scores were derived from this based on quartile position for each antioxidant. There was no apparent effect of antioxidant status on prostate cancer risk in those carrying 1 or more copies of the Val form of MnSOD, but in those homozygous for the Ala version, a strong diet-gene interaction was evident (11). In this subgroup of men, risk of aggressive prostate cancer changed 10-fold from the highest to lowest quartile of antioxidant score (i.e., the risk was 3-fold larger than average for the men with the lowest antioxidant score but only one-third of average for those with the highest score) (11). The authors of this article suggested a possible mechanism of action to explain the interaction between MnSOD genotype and antioxidant status as follows. Mitochondrial MnSOD defends against potential damage by the superoxide radical by dismutating this into oxygen and hydrogen peroxide, which, in turn, are detoxified by mitochondrial glutathione peroxidase (GPX)—a selenoprotein discussed in greater detail below—and catalase. Inadequate supplies of antioxidants may result in accumulation of hydrogen peroxide leading to tissue damage and increased prostate cancer risk (11).
More recently, nested case-control studies from the Nurses' Health Study and the Physicians' Health Study showed that carriage of the Val variant at codon 143 in the O6-methylguanine-DNA methyltransferase gene (MGMT, which encodes a DNA repair protein responsible for removing alkyl groups from guanine residues) is associated with reduced risk of colorectal cancer in women but not in men (12). In addition, in women but not in men, there was evidence of interactions between the Leu84Phe SNP in MGMT and alcohol intake, body mass index, and postmenopausal hormone use (12). Greater alcohol intake increased risk in women carriers of 1 or more leucine (Leu) alleles, whereas higher body mass index or current hormone use appeared to protect against bowel cancer in women with these genotypes (12).
Another example of diet-gene interactions and cancer risk comes from studies of the micronutrient selenium (Se). There is a body of epidemiologic evidence suggesting that low Se intake is associated with increased risk of cancers (13,14). In addition, a large double-blind trial found that Se supplementation (200 µg/d) led to reduced mortality from colon and prostate cancer (15); this was particularly evident in individuals whose Se status was lowest at the start of trial. Recently, a European study showed that over a 10-y period cancer mortality was lowest in the tertile of individuals with the highest plasma Se (16). Biochemical data show that Se is incorporated into a number of proteins as the amino acid selenocysteine during translation of the mRNA; in humans 25 such selenoproteins have been identified (17). The selenocysteine is encoded by a UGA codon in the mRNA (this normally reads for STOP), and the recoding requires a structure in the 3'-untranslated region (3'UTR) of the mRNA (the selenocysteine insertion sequence or SECIS), a specific tRNA for selenocysteine, and specific binding proteins to allow reading of UGA as selenocysteine (Fig. 2) (18). Many of the physiological functions of Se are thought to result from its presence in selenoproteins. Therefore the genes encoding these proteins and the factors required for Se incorporation are prime targets for SNP studies in relation to Se and susceptibility to disease because, potentially, variations in DNA sequence within these genes could affect selenoprotein function. For example, a C-T variation within the protein coding region of the GPX1 gene leads to a Pro-Leu amino acid change, and this has been reported to affect enzyme activity (19,20). In addition, because Se incorporation involves the 3'UTR of the mRNA, it is possible that SNPs within the region of the gene encoding the 3'UTR, although they would not affect the protein itself, could affect synthesis of the selenoprotein and response to dietary Se (21); SNPs were found in the 3'UTR of both GPX4 (22) and the 15-kDa selenoprotein (23). Detailed studies of SNPs in the factors involved in selenoprotein synthesis (SBP2, selenocysteine synthestase 2, and EFSec) have not been carried out, although recently a rare mutation on the SBP2 gene was identified (24). Selenoprotein P contains multiple selenocysteines, and knockout studies indicate that it has a major role in Se transport in the body (25). SNPs in selenoprotein P could therefore affect expression and function of a range of selenoproteins. An SNP within the protein-coding region of this gene was reported (26,18), but further studies are required to define its functionality.
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The data that will emerge from studies of cancer susceptibility in terms of multiple SNPs and nutrients will require complex bioinformatic analyses to define the key factors. Ultimately we would wish to model the contribution of these factors to metabolism and disease susceptibility and define the contribution of different SNPs, as has been done for lipid metabolism (31). To describe the interaction of genetic and nutrient factors in cancer susceptibility, epidemiologic and association studies are not enough: it will be essential to integrate association and functional studies.
Susceptibility genes
Studies of twins provide a powerful means of quantifying the contribution made by genetics to cancer risk. In a landmark study of 44,788 pairs of twins from 3 Scandinavian countries, Lichtenstein et al. (32) used statistical modeling to estimate the relative importance of heritable and environmental factors in causation of cancer at 11 sites. Among the 10,803 people diagnosed with at least 1 cancer, the twin of a person with cancer had an increased risk of having the same cancer (32). However, Lichtenstein et al. concluded that nonshared environmental factors accounted for 60% of the variance in risk for most cancers and that inherited genetic factors make a relatively minor contribution (between one-fifth and one-third) to susceptibility to most types of neoplasm. The familial aggregation of common cancers is thought to be a consequence of inherited susceptibility, and this hypothesis has stimulated the search for low-penetrance cancer susceptibility alleles for >2 decades (33). Until recently, much of this effort used the candidate gene approach, which targets genes in pathways such as carcinogen metabolism or antitumor immune response (33). Although there is now a large literature in this field, few SNP-cancer associations have been established unequivocally (33). Houlston and Tomlinson (34) reviewed 50 studies of effects of SNPs in 13 genes on bowel cancer risk and reported 16 significant (P < 0.05) associations, but only 3 were observed in >1 study. Similarly, in 46 studies of associations between SNPs in 18 different genes and breast cancer risk, 12 statistically significant associations were found, but none was reported by >1 study (33). Many of the individual studies considered in these reviews were relatively small, and some lacked evidence that the polymorphism was functional (i.e., that the polymorphism affected the structure, activity, or level of expression of the encoded protein) (33).
Whole genome mapping
The scale and nature of human genetic variability have been well described by major mapping exercises such as those carried out by the International SNP Map Working Group and by the International HapMap Consortium, which also provided tools for more extensive genetic association studies (35). As an example, the Cancer Genetic Markers of Susceptibility (CGEMS) Project, launched in 2005 and expected to run for 3 y at a cost of $14 million, will use ultrahigh-throughput genotyping to identify genetic variants that increase susceptibility to prostate and breast cancer (36). The strategy is to undertake whole genome scans of at least 550,000 SNPs in nested case-control studies of breast and prostate cancer from large ongoing, population-based cohort studies. Given the very large number of SNP comparisons, many false-positive signals are expected, so the study design includes 4 sequential replication studies that should narrow the search to perhaps 20–50 loci for each cancer site. Such genome-wide scans may identify either large numbers of gene variants, each of which makes quite a modest contribution to risk, or a much smaller number of larger-effect variants that have escaped detection. An alternative strategy is to undertake mapping studies in rodents using inbred strains that differ markedly in their susceptibility to cancers at various sites and, when susceptibility genes are discovered, to study the roles of their homologs in humans (37).
Although recognizing that environmental factors contribute to cancer risk, such gene-environment interactions are often seen as second-order questions to be addressed when the susceptibility alleles have been identified. Some have urged caution about such an approach, arguing that it overlooks the importance of key environmental factors including diet and lifestyle (38). In the case of type 2 diabetes, which has a number of parallels with cancer in that it also appears to be a polygenic disease with strong gene-environment interactions, O'Rahilly et al. (39) argued for inclusion of robust measurement of dietary and physical activity exposure in studies of genetic susceptibility to type 2 diabetes because neglecting environmental exposures not only may attenuate but also may obscure important genetic effects if the effect of genotype differs markedly according to lifestyle. It remains unclear how knowledge of the anticipated genetic variants identified through whole genome scanning can be translated into clinical benefit. Because these polymorphisms are likely to be common, and each is likely to have relatively small effects, the design and conduct of a randomized trial to test the efficacy (and safety) of novel genotype-based chemoprevention agents will be challenging (38).
Measurement of dietary exposure
Characterization and quantification of habitual dietary exposure have long been recognized to pose significant practical difficulties: all existing approaches (e.g., food diaries and food frequency questionnaires) that rely on subjective recording or recall of eating behavior have important limitations, particularly when being used in (molecular) epidemiologic studies. For studies of diet-gene interactions and cancer risk, better tools are needed to provide robust, objective information on dietary exposure (40), if possible using biomarker techniques that do not require study participants to provide dietary intake data.
The potential of the metabolomics approach for characterizing dietary exposure
Metabolomics uses a number of separation techniques to characterize and sometimes identify the many thousands of metabolites in biofluids such as blood and urine. The application of metabolomics in human nutrition is generating a great deal of interest, especially in helping to understand the relations between nutrition and health (41). In addition, because human foods and their circulating or excreted metabolites contain a wide range of metabolomic signals, the metabolomic approach offers a novel means of characterizing and perhaps quantifying dietary exposure. Metabolomics builds on existing attempts to use individual compounds as exposure biomarkers (e.g., urinary nitrogen and sodium as markers of protein and salt intake, respectively). However, this approach is potentially much more powerful in that measuring many signals may make it possible to identify intakes of individual foods or eating patterns through their characteristic fingerprints. Such dietary characteristics have been identified in 1H NMR studies of urine samples from healthy British and Swedish subjects (42) and from participants in the INTERMAP Study from Japan, the United States, and China (43). Although a great deal of basic work remains to be done to develop the metabolomics approach, it shows considerable promise as a means of assessing recent dietary exposure. Characterizing longer-term (or habitual) exposure presents greater challenges.
Epigenomic marking as a record of dietary exposure
Because most cancers occur at older ages (6), a better understanding of the interactions among diet, genetic polymorphisms, and cancer risk will require evidence of dietary exposure over decades. This huge challenge cannot be addressed by any of the dietary biomarker techniques currently in use but might be tractable by building on emerging knowledge of the effect of environmental exposures on epigenetic markings. The observation that monozygotic twins are epigenetically indistinguishable in early life but that with time epigenetic markings (the patterns of DNA methylation and of histone acetylation) become more discordant (44) provides powerful evidence that these markings may provide a cumulative record of environmental exposure. This hypothesis is strengthened by the finding that epigenetic markers were more distinct in twins who had different lifestyles and who had spent more time living apart (44). Evidence from a variety of organisms shows that environmental exposure results in altered epigenetic marking that is maintained over substantial periods of the organism's life. For example, many plants flower only after sustained exposure to cold (winter), and it is now known that the memory of winter is encoded by an altered pattern of methylation of lysine residues in histone H3 (45). Exposure to DNA-damaging agents also induces epigenetic changes in plants and animals [reviewed by Richards (46)]. Intriguingly, the adverse responses to stress that are observed in rats whose mothers display poor nurturing are linked with altered patterns of hippocampal DNA methylation (47). These changes in methylation marks can be reversed by cross-fostering and by central administration of both drugs (47) and nutrients (48). Evidence is also accumulating of the effects of early-life supply of nutrients (49) and other food-derived bioactive compounds (50) on epigenetic marking in rodents.
This fragmentary evidence suggests that altered epigenetic marking may be a means through which environmental (including dietary) exposures are received, recorded, and remembered by the cell. If this is so, interrogation of the epigenome could be a means of revealing the history of environmental exposures to which the individual has been exposed over a lifetime. The explosion of interest in understanding epigenetic regulation of gene expression and its implications for risk of cancer and other common human diseases (51,52) and the development of higher-throughput techniques for assessing epigenetic marking have paved the way for an international consensus that a human epigenome project (akin to the Human Genome Mapping Project) is needed (53). Such an enterprise promises to provide an enormous resource of information on the nature and variability of human epigenomic marking. Epigenome databases would be invaluable in attempts to unravel the linkages between environmental exposure and epigenomic markings that could revolutionize the assessment of long-term dietary exposure and thus studies of diet-gene interactions and cancer risk.
Testing diet-gene interactions
All studies of diet-gene interactions and cancer risk have been observational (i.e., they provide evidence of associations among dietary factors, genotype, and disease). Although very useful in generating hypotheses, for evidence of causality, the next stage will be to design appropriate intervention studies to test specific hypotheses. Such studies should include prospective genotyping and randomization of treatments to individuals with known genotypes. Where there is only 1 genetic variant of interest, and this is relatively common, then this approach should not present significant additional burden on the recruitment and intervention teams. However, if a number of genes are involved (as is likely to be the case for a complex disease such as cancer), then the complexity in study design and challenges in recruitment escalate rapidly (54). Given that dietary studies with primary cancer as the endpoint are unlikely in the foreseeable future, the challenges are to identify and develop biomarkers that can be used as alternative endpoints in intervention studies.
Surrogate endpoints
A major bottleneck for all intervention studies of diet-gene interactions in cancer prevention is the absence of robust, validated surrogate endpoints. This is in contrast with some other major noncommunicable diseases, notably cardiovascular disease and type 2 diabetes, where surrogate endpoints are well established and facilitate hypothesis testing. A recent review by Osborn and Alquist (55) concluded that stool-based markers that target exfoliated cells are likely to have high discriminant potential for detection of colorectal cancer. These sloughed cells contribute 100 ng human DNA/g feces, which is equivalent to 0.01% of the total DNA (56). Exfoliated human cells in stool (or the DNA they contain) have been the target for development of several novel bowel cancer markers including total human DNA, which may be present in considerably higher concentrations in those with bowel cancer (57,58); genetic mutations and other genomic damage (59,60); abnormal protein expression (61); and aberrant epigenetic markings (62,63). For developing surrogate diet-related endpoints for use in intervention studies, the focus should be on molecular changes that precede the appearance of clinical neoplasia. Given the emerging evidence for the significance of aberrant epigenetic marking as a causal component in the etiology of cancer (51,64) and the likelihood that these markings are particularly sensitive to environmental (including dietary) exposure, there is a compelling case to develop improved technologies for detecting and quantifying aberrant DNA methylation in stool as a surrogate endpoint.
Recently, Polley et al. (65) used a proteomics approach to identify genes that are differentially expressed in the colorectal mucosa of individuals at enhanced bowel cancer risk. They showed that protein expression in the macroscopically normal mucosa of individuals with polyps or cancer is different from that in the mucosa from individuals with no evidence of intestinal neoplasia (65). This provides evidence of a field change at the level of gene expression and offers the opportunity to identify novel molecular biomarkers that could be used as surrogate endpoints in intervention trials designed to test diet-gene interactions.
Individual risk of neoplasia depends on complex interactions among genetic inheritance, a range of exposures both in utero and in postnatal life, and the play of chance. As with other complex diseases such as cardiovascular disease and type 2 diabetes, genome-wide scans will probably reveal novel polymorphisms and haplotypes that modify risk. However, given the large body of epidemiologic evidence that dietary exposure explains a significant proportion of cancer risk at several sites, it will be important to characterize dietary exposure and to investigate a much wider range of diet-gene interactions. Such studies present challenges in characterizing long-term dietary exposure and in the development of robust surrogate endpoints, but the application of emerging biological methodologies including metabolomics, epigenomics, and proteomics appears to offer potential ways forward.
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FOOTNOTES |
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2 Author Disclosure: No relationships to disclose.
3 Research on diet-gene interactions and cancer risk in our laboratories is supported by grants from the Biotechnology and Biological Sciences Research Council (13/D15721), the Food Standards Agency (No5041) and the World Cancer Research Fund (2000/10; 2002/14).
6 Abbreviations used: 3'UTR, 3'-untranslated region; CGEMS, Cancer Genetic Markers of Susceptibility; GPX, glutathione peroxidase; MGMT, O6-methylguanine-DNA methyltransferase; MnSOD, manganese superoxide dismutase; SECIS, selenocysteine insertion sequence; SNP, single-nucleotide polymorphism.
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