Molecular genetics of cancer susceptibility

Studies on the role of genetically polymorphic enzymes like cytochrome P450 1A1, arylamine N-acetyltransferase 2 or glutathione S-transferase M1 as ca ncer susceptibility factors date back more than 20 years, and some associat ions have been confirmed in several studies and meta-analyses. Overall, the extent of risk modulation due to these polymorphisms is only moderate but remains epidemiologically relevant. The role of some of these polymorphisms in human health may even be ambiguous: rapid acetylation, for example, pro tects from urinary bladder cancer but appears to increase the risk of laryn geal, lung and colon cancer. The first genetic polymorphisms in xenobiotics transporters such as P-gp (MDR1) and MRP2 have recently been identified. T hese polymorphisms may have great impact as cancer susceptibility factors a s well as factors modulating the out-come of cancer treatment. Enzymes invo lved in generation or detoxification of reactive oxygen species also have t o be considered; one of these enzymes, myeloperoxidase, constitutes a relat ively strong lung cancer risk factor, as confirmed in 4 independent studies . Other genes, including those coding for DNA repair enzymes, signal transd uction and cell growth regulation, may ultimately prove more important than the metabolic enzymes as cancer susceptibility factors. Study designs in m olecular genetic epidemiology are evolving; large ongoing prospective trial s increasingly allow confirmatory nested case control studies to be perform ed. However, carefully controlled, large case-control studies will remain t he mainstay in molecular genetic epidemiology. Molecular genetic epidemiolo gical evaluation of response to chemoprevention as well as response to the adverse events of cancer chemotherapy are likely to provide results that ma y be useful for individualized prevention and treatment in the near future. Since routine genotyping of all persons is now feasible, something like a genotype passport may soon become reality, and molecular and clinical epide miological studies will have to provide the basis for understanding how to use genotype data for the benefit of the population. Copyright(C) 2000 S. K argerAG. Basel.