Androgen metabolism and prostate cancer: Establishing a model of genetic susceptibility

The prostate is an androgen-regulated organ, which has led to longstanding interest in the role of androgens in prostate carcinogenesis. Although evid ence of a hormonal etiology for prostate cancer is strong, it is almost ent irely circumstantial. Much of the problem in proving a causal relationship relates to the continued difficulties in reliably measuring human tissue-sp ecific exposure to endogenous steroid hormones. The international and racia l-ethnic variations in prostate cancer incidence, combined with the effects of migration on risk patterns, have suggested that genetic factors play a central role in determining prostate cancer risk. We are developing a polyg enic model of prostate carcinogenesis, focused around a series of genes inv olved in androgen biosynthesis, transport and metabolism. We have begun to develop this model by utilizing sequence variants to study how polymorphic markers in two genes (SRD5A2 and AR) are related to prostate cancer risk wi thin and between racial-ethnic groups. We are now collaborating with the Wh itehead Institute/MIT, Center for Genome Research, to screen for single nuc leotide polymorphisms in additional genes relevant to the androgen pathway and prostate cell growth. The model when fully developed can potentially pr ovide a basis for targeting populations for screening interventions and for implementing primary preventive strategies.