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 evidence of a hormonal etiology for prostate cancer is strong, it 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 hormones. The international and racial-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 polygenic model of prostate carcinogenesis, focused around a series of genes involved 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 within and between racial-ethnic groups. We are now collaborating with the Whitehead Institute/MIT, Center for Genome Research, to screen for single nucleotide polymorphisms in additional genes relevant to the androgen pathway and prostate cell growth. The model when fully developed can potentially provide a basis for targeting populations for screening interventions and for implementing primary preventive strategies.