Genetic Analysis of Cases, Controls, and Families With Prostate Cancer

The notion that there are prostate cancer susceptibility genes has since been suggested by case-control, cohort and twin studies. The effect is strongest among first-degree relatives, where the relative risk estimates range from 1.7 to 3.7. Families reporting younger ages at diagnosis and multiple relatives with prostate cancer were demonstrated even higher relative risks. For example, compared to men with no family history, men with three or more first-degree relatives with prostate cancer have almost an 11-fold increased risk. Although the majority of studies focused on Caucasians, similar elevations in risk associated with a family history of disease have been reported for Asian and African Americans. While the majority of the data seems to point towards autosomal dominant genes, evidence for an X-linked or recessive inheritance has also been reported.

During the last decade, others and we have been devoted to the search for hereditary prostate cancer (HPC) loci either by linkage or by association with candidate genes. A generally agreed upon definition of HPC families now exists. These are families in which there is either: 1) prostate cancer in three or more first-degree relatives; 2) prostate cancer in three successive generations; or 3) a cluster of two relatives diagnosed at less than or equal to 55 years.

Armed with these criteria, others and we have collected large data sets of likely hereditary families and undertaken genome wide scans. However, locus heterogeneity issues have made the task difficult. There are clearly many genes that contribute to prostate cancer susceptibility, and many are likely to be weakly penetrant. We have stratified the data derived from our genome scan by a number of likely factors such as age at diagnosis, number of affected men, founder effects aggressiveness of disease, and presence of other cancers in the family to develop more homogeneous datasets. We propose to continue those sorts of studies, as well as focus on cloning genes in regions we and others have identified to date. To test hypotheses that certain variants are associated with prostate cancer susceptibility or progression of disease, will also conduct association studies in a population-based, case control study of middle aged men with prostate cancer. This will allow us to test the putative association of candidate genes and SNPs in prostate cancer susceptibility, aggressivity, and long-term outcomes.