Identification of Prostate Cancer Genes
Condition: Prostate Cancer
MeSH terms: Prostatic Neoplasms
Study type: Observational

Summary: 
      This study will identify genes that predispose men to prostate cancer and affect the rate and
      type of disease spread, the aggressiveness of the disease, and the long-term outcome. Several
      studies show there is a genetic component to prostate cancer susceptibility, and that a
      first-degree relative with prostate cancer increases a man's risk 2- to 3-fold compared to
      those without a family history. The risk is significantly higher if the relative was
      diagnosed at younger than 65 years of age, or if three or more first-degree relatives are
      affected.

      The study will try to locate prostate cancer genes in DNA samples using two methods: linkage
      analysis and association studies. Traditionally, the search for a disease gene begins with
      linkage analysis, in which the aim is to find the rough location of the gene relative to
      another DNA sequence, called a "genetic marker," whose position is already known. In genetic
      association studies, genes from a large number of patients are compared with healthy controls
      who are matched by age, race, and geographic region.

      DNA samples for this study come from patients in the two following studies at the Fred
      Hutchinson Cancer Research Center, Seattle, Washington:

      Family study: Participants are families with prostate cancer who have: 1) three or more
      first-degree relatives with prostate cancer; 2) three generations with prostrate cancer
      either through the maternal or paternal side of the family; or 3) two first-degree relatives
      with prostate cancer diagnosed before age 65 or who were African American.

      Population-based study: Participants are patients with prostate cancer and matched healthy
      control subjects.

      The identification of prostate cancer genes important in susceptibility to the disease and
      its aggressiveness may permit earlier detection and development of more directed and
      effective treatments based on underlying genetics.
    

Detailed description: 
      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.
    

Keywords: Mutation; Cancer Genetics