Molecular genetic alterations as intermediate end points in chemoprevention studies

It is generally accepted that carcinogenesis is related to the accumulation of genetic damage in somatic cells. In support of this concept, numerous studies have identified and characterized genes that are mutated or deleted in carcinogenesis. Some of these genetic alterations occur very frequently, and therefore it is theoretically possible to use them as diagnostic tools or as intermediate end points for chemoprevention studies. This is particularly relevant for some animal models, in which certain genetic alterations are found at a frequently close to 100%. In contrast, specific genetic alterations normally occur less frequently in human cancer, probably because humans are genetically more heterogeneous and are exposed to multiple carcinogens, tumour promoters, and other modifiers of carcinogenesis. Some genetic alterations occur early in tumour development, as in the case of ras mutations in some chemical carcinogenesis models. Similarly, p53 mutations also appear to be a frequent and early event in ultraviolet light (UV)-induced skin tumours in mice and possibly in humans. However, in other neoplasias such as prostate cancer, p53 alterations occur at late stages of tumour development. Alterations that occur early in neoplastic development may be valuable as early markers of tumour development, whereas those that occur late in development may be useful for determining the action of chemopreventive agents on tumour progression. Although the use of genetic markers as intermediate end points of cancer prevention studies has not been completely developed, it has great potential. The development of simple and sensitive molecular techniques such as the polymerase chain reaction and in situ hybridization has opened the possibility of using these markers in large-scale cancer prevention studies.