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.
Elaine A Ostrander, Ph.D.
National Human Genome Research Institute (NHGRI)
United States: Federal Government
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