Genetic susceptibility to prostate cancer: Association and linkage studies of candidate genes in the androgen metabolism pathway

Abstract

Prostate cancer is the most frequently diagnosed noncutaneous cancer in the men of many industrialized countries. Although environmental factors have been implicated in the etiology of prostate cancer, the involvement of genetic factors has also been clearly demonstrated. The effect of heritable factors has been estimated to be 42% for prostate cancer and was highest among all neoplasms. Segregation and linkage studies have mapped several major prostate cancer susceptibility loci that are believed to account for about 9% of all prostate cancers. In addition to major gene effects, common polymorphisms that result in minor quantitative and qualitative functional differences in gene products may modify the risk of a complex disease like prostate cancer. Among numerous candidate genes, the genes in the androgen metabolism pathway are particularly compelling because of the vital role of androgens in the etiology of prostate cancer. Several genes in the androgen pathway have been under intense examination as candidate genes for prostate cancer. In this study, six candidate genes: AR, CYP17, CYP19, CYP3As, SRD5A2, and HSD3Bs were investigated regarding to their possible role in the pathogenesis of prostate cancer, by both linkage study and population-based association study in 159 hereditary prostate cancer (HPC) families, 249 sporadic prostate cancer cases, and 211 unaffected controls. In the analyses that included all HPC families, substantial evidence for linkage was found in the chromosomal regions of HSD3Bs and CYP17 genes, but not in the regions harboring AR, CYP19, and SRD5A2 genes. Stratified linkage analyses revealed evidence for linkage at HSD3Bs and CYP17 loci among a subset of families with older mean age of diagnosis, and in families with ≥5 affected members. Stratified analysis of families with younger mean age of diagnosis revealed linkage to the AR gene. To determine the contribution of genetic variants in candidate genes with evidence of linkage, the allele and genotype frequencies were compared in the case control studies. Statistically significant associations were found between three SNPs (HSD3B1-N367T, HSD3B2-c7519g, and AR GGC repeats) and the risk of prostate cancer. The results of this study clearly supports other lines of evidence underscoring the importance of the androgen pathway in the etiology of prostate cancer, and the effects of genetic variants in the genes of the androgen pathway on an individual's risk of prostate cancer.