Genetic polymorphisms

F. F. Kadlubar, Ph.D.

Division of Molecular Epidemiology, National Center for Toxicological Research, Jefferson, AR 72079 USA

Genetic polymorphisms provide us with the ability to predict inter-individual differences in susceptibility to clinical disease. Biomarkers of susceptibility include: polymorphisms in drug/carcinogen metabolism, in DNA repair capacity, and in genes that control cell growth. Wide variations in drug/carcinogen metabolism have been widely investigated and clearly shown to be an important determinant of individual cancer susceptibility and adverse drug reactions. Such polymorphisms in drug/carcinogen-metabolizing enzymes may be due to heritable and/or to environmental factors; and the modern application of metabolic phenotyping and genotyping methods to epidemiological studies has provided new insights into such gene-environmental interactions. Polymorphisms in DNA repair or processing of DNA damage have long been evident from rare hereditary disorders involving defective DNA repair or chromosomal stability. Today, about 130 different genes have been shown to be involved in DNA excision or base repair and polymorphisms in gene-specific DNA adduct repair have been correlated with biological outcomes (mutations, drug sensitivity). Moreover, lower DNA repair proficiency has recently been associated with increased susceptibility to cancers of the skin, brain, lung, stomach, breast, bladder, head/neck, and colon. While over 100 genes have been identified that serve as positive (proto-oncogenes) or negative (tumor suppressor genes) regulators of cell growth, as well as the cell cycle and apoptosis (e.g., cyclins, CDKs, cytokines, chemokines, their receptors, caspases, etc.), these have been largely associated with rare hereditary disorders involving greatly increased human cancer susceptibility. However, while the common polymorphisms in these genes, which include p53, p21, Her/neu, ras, APC, IL-10, and cyclin D1 (CCND1) have not yet received much attention, initial studies indicate that these may be associated with breast, endometrial, ovarian, bladder, colon, lung, thyroid, gastric, nasopharyngeal, esophageal, multiple myeloma, and head/neck cancer. It should be emphasized that although these common genetic polymorphisms do not in themselves confer high individual cancer risk (low penetrance), they involve a large proportion of the population (high prevalence). Thus, their attributable risk in any given population can be quite high and the importance of public health measures that result in lowering risk in the susceptible subgroup is of paramount importance because it can affect a larger number of people, as compared to those rare defects (low prevalence) that greatly increase disease risk (high penetrance) but only in a few individuals (low attributable risk), such as BRCA1 and BRCA2. In addition, the combination of several high risk alleles in a single individual, i.e. gene-gene interactions, can result in substantial increases in relative risk. When combined with a known carcinogen exposure (e.g., dietary heterocyclic amines or environmental aromatic amines), the probability of developing cancer in such persons becomes extremely high. Some examples of such gene-gene-environmental interactions from our ongoing molecular epidemiologic studies of breast and colon cancer will be presented.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Molecular Genetics & Therapy - 2.