Mechanisms of carcinogenesis and individual susceptibility to cancer.

The population can be divided into four groups, or "oncodemes," depending on the relative contributions of environment and genetics to their risk of cancer. These oncodemes are: 1) background (random mutations in normal people); 2) environmental (environmental carcinogens acting on normal people); 3) environmental/genetic (environmental carcinogens acting on genetic susceptibility); and 4) genetic, with genetic susceptibility being more important than environmental exposure. Most cancer probably occurs in oncodemes 2 and 3. However, the contribution that genetic susceptibility to cancer makes to the total cancer burden is unknown. Genetic susceptibility may be important in occupational settings, where exposure to carcinogens is presumed to be restricted to concentrations believed to confer "acceptable" risks. This approach takes no account of individual susceptibility. The range over which metabolic polymorphisms exert their effects suggests that differences in pharmacogenetics between individuals may be important in occupational carcinogenesis. If this range were extrapolated to risk of human disease, at a given exposure one person might be 10-200 times more sensitive than another. Several metabolic polymorphisms have been linked to susceptibility to cancer. For some of these polymorphisms, genes have been cloned and genotypic tests based on use of the polymerase chain reaction have been developed. Limited data suggest that the effects of these polymorphisms on human cancer are complex. The genotypic testing of individuals occupationally exposed to carcinogens may provide firmer information on the relative contributions of nature and nurture on chemically induced cancer. The use to which such information is put demands wide debate.