(Kinzler and Vogelstein, 1996). However, only a small proportion of colorectal cancers are attributable to inheritance of these rare, highly penetrant mutated genes. Epigenetic changes, such as alterations in DNA methylation (e.g., CpG island methylator phenotype, or CIMP) and gene expression, also may play a critical role in the development of this malignancy (Baylin et al., 1998). It is evident too that variability in carcinogen-metabolizing genes influences the risk of colorectal neoplasia in humans (Gertig and Hunter, 1998; Hussain and Harris, 1998a; Pereira, 1998).
It is clear that susceptibility to colorectal cancer is related to interindividual variability in biotransformation of endogenous and exogenous substances, as well as in DNA repair and cell cycle control. Common genetic variation may enhance susceptibility to environmental carcinogens by altering the rates of activation and detoxification of carcinogens. The interactions of environmental factors with metabolic polymorphisms may act via a model in which the exposure alone, but not the variant genotype alone, increases disease risk; however, exposure interacts with the variant genotype to further increase risk in the exposed individuals (Vineis, 1997). The same interaction can also modulate disease pathogenesis in that exposure and susceptibility factors may alter the effects of other risk factors, such as folate intake, methylenetetrahydrofolate reductase (MTHFR), CIMP, selenium, or celecoxib intervention, and cyclooxygenase (COX) upregulation, on adenoma recurrence. An example of such an interaction is the relationship between alcohol intake, folate, and MTHFR. Classification of subgroups of the population into those who may be more vulnerable to the effects of certain carcinogens may also have important implications beyond risk assessment. Through the identification of an increased risk in certain subgroups, disease risk factors may be better defined. However, to date, sample sizes for most studies attempting to uncover gene–environment interactions have been small, limiting the potential for detecting significant findings.
CIMP as a Marker of Gene Methylation. As stated previously, a genetic basis for cancer has been established with the assumption that the age (and mutagen exposure) related accumulation of somatic mutations accounts for the increased incidence of cancer with age (Ames et al., 1993). The actual rate of mutation accumulation in aged tissues is more uncertain, with some investigators finding lower than expected mutation rates (Warner and Price, 1989; Bohr and Anson, 1995), possibly reflecting the presence of additional mechanisms for activation and/or inactivation of genes important in the carcinogenesis process. In the past few years, there has been renewed interest in epigenetic mechanisms in carcinogenesis (Jones, 1996; Baylin et al., 1998). Epigenetics refers to the study of changes in gene expression that can be mitotically inherited, without associated changes in the coding sequence of the affected genes. Aging and transformed cells show profound changes in gene expression, many of which cannot be accounted for genetically (Sager, 1997). Methylation of DNA within