Public Health Nutrition: 4(2B), 485±491 DOI: 10.1079/PHN20011135 Diet, genetic susceptibility and carcinogenesis Paolo Vineis* Unit of Cancer Epidemiology, University of Torino and CPO-Piemonte, via Santena 7 10126 Torino, Italy Abstract At least six types of gene±environment interactions (GEI) have been proposed (Kouhry and Wagener, 1993). In the first type, neither the environmental exposure (EE) nor the genetic risk factor (GRF) have any effect by themselves, but interaction between them causes disease. This is the case of phenylalanine exposure and the phenylketonuria genotype. Type 2 is a situation in which the GRF has no effect on disease in the absence of exposure, but exacerbates the effects of the latter. This is the most important type of GEI in relation to metabolic susceptibility genes and human carcinogenesis. The third type is the converse of the second (EE is ineffective per se, but enhances the effect of GRF). Type 4 occurs when both EE and GRF increase the risk for disease, but the combination is interactive or synergistic: an example is the interaction between Xeroderma Pigmentosum and UV radiation. Types 5 and 6, according to the classification proposed by Kouhry, refer to cases in which the GRF is protective. The model of GEI that is emerging as the most important in chemical carcinogenesis refers to metabolic susceptibility genes. The general population can be divided into subgroups depending on their susceptibility to the action of carcinogens, based on their ability to metabolize such compounds to electro- Keywords philic, reactive metabolites (which form adducts with DNA), or, respectively, Diet electrophobic metabolites that are excreted. The present contribution is a short Genetic susceptibility review of the relevant literature, with particular emphasis on some polymorph- Carcinogenesis isms involved in dietary exposures. In addition, the practical implications of Metabolic polymorphisms genetic testing in this field are discussed. DNA repair Cancer genes protein function (a DNA repair enzyme) are probably mild. It is becoming clear that single highly-penetrant mutations Concerning category (b), many metabolic polymorph- in `cancer genes' explain a very small proportion of isms are a clear example. Subjects with the GSTM1 cancers1 (penetrance is the strength of the association `null' genotype are frequent (about 50% of the between a mutation and the risk of disease, expressed by population), have a serious genetic change (a deletion the proportion of the mutation carriers who develop the of the entire gene), but a slightly increased risk for phenotypic manifestations). This consideration arises some forms of cancer. Rare and highly-penetrant both from empirical observation and from general mutations in `cancer genes' may act without interacting scientific knowledge. Highly-penetrant gene mutations ± with external exposures; this is not necessarily the rule, that confer an exceptionally high risk of cancer in the since XP is itself one of the best examples of gene± carriers ± represent the tail of a distribution that includes: environment interaction, and there is evidence that (a) more common mutations in the same cancer genes dietary factors may have a greater impact in women (polymorphisms), that have a less disruptive effect on the with one or more first degree relatives with breast protein function; or (b) rare or common mutations in cancer than in women without familiarity3. However, genes that are less directly involved in the cancer process. gene±environment interactions are the rule in the case There is increasing evidence that both categories may of low-penetrance genes. play a role in carcinogenesis. Mohrenweiser and collea- There are not many examples of interaction between gues 2 have shown that even genes involved in rare and genetic susceptibility, dietary exposures and the risk of disruptive conditions such as Xeroderma Pigmentosum cancer. I will review two prominent examples in the show common polymorphisms whose effects on the following. *Corresponding author: Email [email protected] q The Author 2001 Downloaded from https://www.cambridge.org/core. 30 Sep 2021 at 09:35:54, subject to the Cambridge Core terms of use. 486 P Vineis Metabolic polymorphisms: examples of interaction The polymorphism in MTHFR, plasma tHCY, and folate between dietary components and genetic using baseline blood levels were examined among 293 susceptibility Physicians' Health Study participants who developed myocardial infarction (MI) during up to 8 years of Methylenetetrahydrofolate reductase follow-up and 290 control subjects. Compared with polymorphism those with genotype A/A, the relative risk (RR) of MI Common genetic polymorphisms have been reported in among those with A/V was 1.1 (95% CI, 0.8 to 1.5), and it the gene encoding methylenetetrahydrofolate reductase was 0.8 (0.5 to 1.4) for the V/V genotype; none of these (MTHFR), the enzyme that produces 5-methyltetrahydro- RRs were statistically significant. However, those with folate (5-methyl-THF) required for the conversion of genotype V/V had an increased mean tHCY level homocysteine to methionine. In individuals with the val/ mean ^ SEM; 12:6 ^ 0:5 nmol=mL; compared with val genotype, functional effects include elevations in those with genotype A/A 10:6 ^ 0:3 P , :01: This plasma homocysteine and differences in response to folic difference was most marked among men with low folate acid supplementation. The metabolic changes associated levels (the lowest quartile distribution of the control with such genotype have been reported to modify the risk subjects): those with genotype V/V had tHCY levels of for chronic disease (e.g., vascular disease and cancer) and 16:0 ^ 1:1 nmol=mL; compared with 12:3 ^ 0:6 nmol=mL neural tube defects in conjunction with folate deficiency. P , :001 for genotype A/A. Therefore, gene±environ- Folate intake requirements may be different in affected ment interaction might increase the risk by elevating individuals relative to normal or heterozygous indivi- tHCY, especially when folate intake is low9. duals. The complex interaction between this common genetic polymorphism of MTHFR and folate intake is the Colon cancer, heterocyclic aromatic amines and focus of intense investigation4. NAT2 In a study in the U.S. an inverse association of the val/ val polymorphism in the MTHFR gene was associate with Heterocyclic aromatic amines are a group of experimental colorectal cancer. The inverse association of methionine carcinogens that are formed when meat is fried. They are and adverse association of alcohol with colorectal cancer metabolized via pathways similar to those for other were stronger among val/val individuals. These inter- arylamines like 4-aminobiphenyl or 2-naphthylamine, i.e. actions were not present in studies of colorectal N-acetylation and N-oxidation. N-acetylation is performed adenomas5,6. In another study, the association between by the polymorphic non-inducible enzyme N-acetyltrans- the same allele of the MTHFR gene and ischemic stroke in ferase, under control of the genes NAT1 and NAT2; an elderly Japanese population was examined. In 256 N-oxidation is performed by CYP1A2, which is an stroke patients and 325 control subjects, the frequencies inducible enzyme of the mixed-function oxidase group. of the allele were 0.45 and 0.32, respectively. The odds A positive association between the `rapid acetylator' ratios and 95% confidence intervals adjusted for the other phenotype and the risk of colon cancer has been shown risk factors were, respectively, 1.51 (1.02 to 2.23) for the in some studies but not in others (Table 1). The adenine/valine genotype and 3.35 (1.94 to 5.77) for the N-acetyltransferase phenotypes are approximately val/val genotype compared with the adenine/adenine bimodally distributed, with around 40% of persons in genotype7. European populations being `rapid acetylators'. As Table Moderate elevation of plasma total homocysteine 1 shows, the slow acetylator phenotype seems to exert a (tHcy) is a strong and independent risk factor for rather strong protective effect (OR around 0.3±0.4), coronary artery disease (CAD). It can result from genetic compared to the rapid acetylator phenotype, in three or nutrient-related disturbances in the transsulfuration or studies based on the phenotype. In one study measuring remethylation pathways for homocysteine metabolism. the phenotype and three studies based on the genotype Studies on the role of the A/V mutation as a risk factor for (i.e. on the identification of mutations in the NAT2 gene), CAD have given conflicting results. In one study, a total of however, no association was found. A particularly 415 subjects, 278 with angiographically documented interesting finding was reported from a study in Aus- multivessel CAD and 137 with angiographically docu- tralia10, where an association between high levels of meat mented normal coronary arteries were included. The consumption and colon adenoma or carcinoma was overall frequency of the MTHFR V/V homozygous detected among rapid acetylators only (Table 1). A genotype was 15.7% (with 52.5% heterozygous and Japanese study looked at the relationship between the 31.8% normal). Subgroup analysis showed no significant NAT2 genotype and mutations in the K-ras oncogene differences between CAD and CAD-free subjects. (Odds Ratio 0:2 for rapid acetylators, 95% confidence However, among individuals with folate levels below interval 0.03±1.0). Overall, these findings can be inter- the median, fasting tHcy was significantly increased not preted as reflecting the greater ability of rapid acetylators only in V/V homozygotes (by 59%) but also in A/V to activate heterocyclic aromatic amines to carcinogenic heterozygotes (by 21% on average)8. derivatives within the colon mucosa. Although such Downloaded from https://www.cambridge.org/core. 30 Sep 2021 at 09:35:54, subject to the Cambridge Core terms of use. Diet, genetics and carcinogenesis 487 Table 1 Relative risks of colon cancer according to the acetylator phenotype: slow vs.