ANDROGEN METABOLISM AND PROSTATE-CANCER - ESTABLISHING A MODEL OF GENETIC SUSCEPTIBILITY

The prostate is an androgen-regulated organ, which has led to longstan ding interest in the role of androgens in prostate carcinogenesis, Alt hough evidence of a hormonal etiology for prostate cancer is strong, i t is almost entirely circumstantial, Much of the problem in proving a causal relationship relates to the continued difficulties in reliably measuring human tissue-specific exposure to endogenous steroid hormone s. The international and racial-ethnic variations in prostate cancer i ncidence, combined with the effects of migration on risk patterns, hav e suggested that whereas environmental factors are likely to be import ant, genetic factors might also play a central role in determining pro state cancer risk. We are developing a polygenic model of prostate car cinogenesis focused around a series of genes involved in androgen bios ynthesis and androgen activation, transport, and metabolism in the pro state. In this developing model, we have initially targeted four genes based on three main criteria: (a) all encode products that play impor tant roles in inducing androgen stimulation in the prostate; (b) all a re polymorphic; and (c) all show substantial allelic variation in the polymorphic marker among the racial-ethnic groups of greatest interest in terms of prostate cancer risk. In addition to studying how the pol ymorphic markers of interest are related to prostate canter developmen t within and between racial-ethnic groups, we are concurrently evaluat ing whether genotypic variations correlate in the anticipated directio n with biochemical parameters in vitro and in vivo. We summarize the d evelopment of this model and the state of knowledge related to each of the genes comprising the current model. We discuss the extent to whic h the current model can explain demographic variation in prostate canc er risk as well as the potential for future expansion of the model to incorporate environmental risk factors as well as additional genes. Th e model, when fully developed, can potentially provide a basis for tar geting populations for screening interventions and/or preventive strat egies aimed at the multigene products or at the genes themselves.