Investigations of specific cancers Bowel cancer

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The descriptive epidemiology of bowel cancer indicates wide variation in cancer incidence rates across the world with the highest rates in Western

Europe, USA, Canada, Australia and New Zealand (Potter and Hunter, 2002). The lowest rates are in parts of South Africa and Southern Asia. Rates have varied marginally by time across most countries but the most notable change has been in Japan where the incidence rate have risen from being among the lowest to among the highest in a couple of generations presumed to be due to the Westernization of diet and lifestyle in that time period. Diet is regarded as being the most important factor influencing cancer risk. A number of aetiological studies have examined individual differences in diet and lifestyle, especially between persons with and without cancer, either through cohort or case-control studies. Among dietary factors, diets high in animal fat and low in fiber, fruit and vegetables are associated with increased risks (Potter and Hunter, 2002). The complexity of diet assessment and the interrelationship of dietary items exacerbates the difficulty of identifying the critical aspects of diet. Several hypotheses have therefore been proposed.

Meat, heterocyclic amines and risk

Epidemiological studies have indicated that meat intake is a risk factor for colorectal cancer. These studies have been varied in design (cohort and case-control), size, population studied, methodology for assessing meat consumption and in their conclusions (reviewed by Potter et al., 1993). Some studies have suggested that red meat is particularly associated with risk of this cancer while others find no effect. Some studies have found protective effects of poultry and fish consumption while the findings of others have not confirmed this. A recent European study, which represents probably the most thorough investigation of this issue to date, found both an increased risk from red and processed meat and a protective effect of fish (Norat et al., 2005). Similar comments of inconsistency can be made about the association between cigarette smoking and colon cancer risk. As qualitatively, if not quantitatively, exposure to tobacco is more readily measured than quantity and preparation style of meat, the inconsistency of the results is surprising. One speculation on the basis of these studies is that members of the public are differentially susceptible to the effects of such exposures.

One of the primary hypotheses concerns interindividual variation in the handling of heterocyclic amines (HAs). HAs are formed when animal protein is cooked at high temperature and are also present in cigarette smoke. Also, HAs are known to be carcinogens in rodents. There are at least three polymorphic enzymes involved in this process, CYP1A2, NAT1 and NAT2 (Kadlubar et al., 1992). To date, genetic polymorphisms have been found in NAT1 and NAT2 which are associated with pheno-typic differences (defined as ''fast'' or ''slow'' depending on the activity of the alleles) in their metabolism. Indeed, several studies have suggested that the fast phenotype of N-acetyltransferase NAT2 may confer susceptibility to colorectal cancer especially in individuals with a diet high in heterocyclic amines such as is contained in well-done meat (see below). Such a relationship could be postulated in terms of NAT2's role in activating such dietary heterocyclic amines.

There are two hypotheses as to how NATs could relate to colorectal cancer risk. The first mechanism involves CYP-mediated N-hydroxylation of arylamines which yields electrophilic intermediates that can be inactivated by NAT acety-lation. The other mechanism suggests that fast acetylators are at increased risk because of the activation of procarcinogens such as HAs. Exposure to HAs is common; such HAs are produced when meat and fish are cooked at temperatures achievable in the household or by smoking. The HAs undergo hepatic N-oxidation and N-glucuroni-dation resulting in conjugated N-hydroxy metabolites which can be transported to the colonic lumen. Within the mucosa, these derivatives can be O-acetylated and can form covalent DNA adducts.

In a small Australian case-control study, RobertsThomson et al. compared colorectal cancer cases and controls (Roberts-Thomson et al., 1996).

The fast acetylator phenotype of NAT2 was associated with 1.8-fold increased risk of colorectal cancer with the highest risk occurred in the youngest group (<64 years of age) of cases. The risk of cancer increased with increasing intake of meat in fast but not in slow acetylators (see Chapter 11).

Other subsequent, marginally larger epidemiological studies have not confirmed precisely the findings of the Australian study (RobertsThomson et al., 1996). A case-control study in the North of England found no difference in the frequency of the fast acetylator genotype between cases and controls (Welfare et al., 1997). There was, considerable heterogeneity in dietary risk factors between fast and slow acetylators. The combination of fast acetylator status and frequent fried meat consumption in cases had an estimated sixfold increased risk of cancer. In the Physicians' Health Study study in the USA, again there was no overall independent association of NAT acetyla-tion genotypes and colorectal cancer risk (Chen et al., 1998). A stronger association of red meat intake with cancer risk among NAT rapid acetyl-ators, especially among men 60 years or older was, however, identified. Among those men who were rapid acetylators for both NAT1 and NAT2, consumption of >1 serving of red meat per day was associated with an estimated sixfold increased risk as compared with consumption of at most 0.5 servings per day. These prospective data are consistent with the suggestion that polymorphisms in the NAT genes confer differential susceptibility to the effect of red meat consumption on colorectal cancer risk although the analyses differ in the precise risk factors considered and found to be discriminating.

Among the larger studies, a further study in the North of England and Scotland found no evidence of variation in risk attributable either to the NAT1 or NAT2 polymorphisms or to meat intake (Barrett et al., 2003). In a case-control study conducted in the USA, the amount of red and white meat consumed was not associated with overall colon cancer risk (Kampman etal., 1999). Processed meat consumption was weakly positively associated with colon cancer risk in men only (odds ratio for highest versus lowest quintile of intake = 1.4, 95% confidence interval = 1.0-1.9). No significant associations with colon cancer risk were observed for different NAT2 gene variants although there were trends in the data for the fast acetylator group.

Slattery et al. (1998) found that NAT2 polymorphisms were not significantly associated with colon cancer, except among older women, in whom the intermediate/fast phenotype was associated with a marginally increased risk (about 40%) of colon cancer. Cigarette exposure was associated with colorectal cancer risk with those smoking a pack or more of cigarettes per day being at an approximately 40% increased risk of colon cancer. No significant interaction between the genotypes and cigarette smoking and colon cancer was found.

This example shows the complexity of testing a biological hypothesis. The limited understanding of the details of the biological pathways, the lack of knowledge of the clearest measurement of exposure, and the difficulties of measuring that exposure all limit the interpretation. The positive findings are of some interest, and of some limited consistency, but clearly the various studies cannot be regarded as complete replications.

Folate and colorectal cancer

A second hypothesis relates folate to bowel cancer risk. This hypothesis unites the observation of low intake and plasma levels of folate and increased use of alcohol from the epidemiological studies as risk factors for bowel cancer. It proposes that abnormalities in folate levels disrupt nucleotide synthesis (and hence biological methylation), as well as double strand breaks and reduces DNA stability (both features of colorectal cancer) (Ames, 1999; Vogelstein et al., 1989). Folic acid is the universal methyl donor in cellular methabolism. Folate deficiency may therefore result in global hypomethylation, which is thought to be an early event in the development of many colorectal tumors.

Germline mutations in mismatch repair genes are associated with greatly increased risks of colo-rectal cancer and cancer at other sites in hereditary non-polyposis colorectal cancer syndrome (HNPCC). Mutation carriers have a notably early onset of colorectal cancer and their tumors display a characteristic phenotype, termed ''microsatellite instability" (MSI). MSI-positive tumors show variant alleles at many microsatellite and mononucleotide repeat genetic sequences. Examination of case series have shown that up to 15% of tumors exhibit this phenotype. MSI-positive tumors are found at young ages, and are often associated with a strong family history. Such tumors have lost mismatch repair capabilities through the inactiva-tion of both alleles, often by loss of heterozygosity of the wild-type allele. However, MSI-positive tumors are found at much greater frequency at older ages, particularly in right-sided tumors and are more common in females. Immuno-histochemical analysis of colorectal cancer tumours shows loss of mismatch repair protein expression (either hMLSH2 or hMLH1) at young ages but predominantly loss of hMLH1 at older ages. This loss is now known to be primarily due to promotor hypermethylation of the hMLH1 gene, leading to defective mismatch repair capabilities (Cunningham et al., 1998). Figure 14.1 shows how loss of expression of hMSH2 and hMLH1 relates to age and gender.

The possibility exists that abnormalities in methylation contribute to colorectal cancer development and that this could involve either folate in the diet, genetic polymorphisms or both. The polymorphism that has been studied in most detail involves the C677T variant of the methylenetetrahydrofolate reductase (MTHFR), which is a regulatory enzyme in the metabolism of folate. The variant T-allele produces a protein with decreased activity. Several case-control studies have found that the TT genotype has a reduced risk of colorectal cancer although these comparisons with the wild-type (CC) genotype have been of marginal significance. The reduced risk is most notable at higher levels of folate intake,

Figure 14.1 The percentage of colorectal tumors showing loss of expression of two mismatch repair proteins, hMSH2 and hMLHl in a population case series of 730 cases (Coggins, unpublished data). The results are presented by gender for hMLHl showing the differences between males (M) and females (F). Small numbers preclude such an analysis for hMSH2.

Figure 14.1 The percentage of colorectal tumors showing loss of expression of two mismatch repair proteins, hMSH2 and hMLHl in a population case series of 730 cases (Coggins, unpublished data). The results are presented by gender for hMLHl showing the differences between males (M) and females (F). Small numbers preclude such an analysis for hMSH2.

with suggestions that the effect is only found in those drinking low amounts of alcohol.

Finally, in a case-control study of smoking and colorectal cancer, the effect of smoking was estimated to be responsible for 21% of the tumors with microsatellite instability suggesting that smoking may have an effect on a pathway influencing or involving methylation (Slattery et al., 2000).

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