A variety of genes are involved in the metabolic pathway of androgens and the mediation of the effects of androgens. Functionally important polymorphisms in genes that encode enzymes involved in androgen metabolism and transport may lead to differences in individual susceptibility to prostate cancer by altering the levels and effects of androgens, as proposed by Ross et al.75 (see Chapter 15) Thus far, studies of androgen-pathway genes and the risk of prostate cancer have focused mainly on sporadic prostate cancer. In addition, studies of HPC have primarily focused on the identification of novel major susceptibility genes. However, we cannot exclude the possibility that mutations (or polymorphisms) in androgen-pathway genes are involved in the etiology of HPC for the following reasons. First, given the biological relevance of andro-gens in the etiology of prostate cancer in general, it is possible that mutations in the andro-gen-pathway genes that significantly affect androgen metabolism may be inherited as high-penetrance susceptibility genes in some families. Second, the androgen-pathway genes may, instead of being major genes, act as modifier genes for major susceptibility gene(s) segregating in high-risk families. Mutations in major susceptibility genes might not reveal their full potential and lead to clinically identifiable prostate cancer (incomplete penetrance) without mutations (or polymorphims) in androgen-pathway genes. Third, before major prostate cancer genes are identified and their roles in the genetics of HPC families fully understood, the possibility that multiple, minor genes are responsible for HPC should not be excluded.
FAMILY-BASED STUDY DESIGN: COMPENSATING FOR THE POPULATION-BASED STUDY DESIGN IN THE INVESTIGATION OF CANDIDATE GENES IN PROSTATE CANCER SUSCEPTIBILITY
The ability of any study design to detect a relationship between a mutation (or a polymorphism) and disease susceptibility is dependent on the frequency and penetrance of the mutation (or polymorphism). Because the underlying influence of DNA sequence variants in the an-drogen-pathway genes is unknown, approaches utilizing multiple study designs are needed to evaluate these genes in the etiology of prostate cancer. Several methodologies, including linkage analysis, the family-based association test, and the population-based association test, can be applied to thoroughly examine the role of candidate genes in complex diseases such as prostate cancer.
A genetic linkage study is one important design to evaluate candidate genes in complex diseases such as prostate cancer. A significant feature of the linkage approach is that it is less sensitive to allelic heterogeneity. If a mutation has a large effect (i.e., high penetrance) and there are multiple such mutations within a gene, a linkage study is likely to detect the effect of such a gene, while population-based association approaches are likely to fail. Information regarding specific sequence variants within a gene is not necessary for linkage studies, while it is essential for association studies. At this stage, it is technically difficult to identify and assess multiple sequence variants due to limited sequence data from large numbers of prostate cancer patients and unaffected control subjects.
To date, most studies have utilized population-based association tests to evaluate the relationship between genetic variants in androgen-path-way genes and the risk of prostate cancer, especially sporadic prostate cancer. A population-based association study is the method of choice to detect mutations with a high frequency but low penetrance. However, as mentioned above, genetic linkage studies and family-based association studies in families with multiple affected members are better designs for detecting mutations with a lower frequency but higher penetrance because the frequency of gene carriers is likely to be higher in these families and there is a higher likelihood that a rare mutation cosegregates with disease in family members carrying the disease. In addition, it is difficult to rule out the effect of population stratification in population-based association studies. A family-based test is free from population stratification and can compensate for the shortcomings inherent to the population-based study design.
Only a limited number of studies have in vestigated the potential impact of androgen-pathway genes on the risk of HPC. Four genes, AR, 3jS-hydroxysteroid dehydrogenase types I and II (HSD3B1, HSD3B2), and cytochrome P-450c17a (CYP17), will be reviewed in the following sections.
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