INVESTIGATION OF HEREDITARY PROSTATE CANCER

The hypothesis of this study is that inherited genes contribute to the susceptibility and development of prostate cancer. The underlying principles of this unique study design are: (1) a population-based approach to identify genes involved in hereditary prostate cancer; (2) focus on the Ashkenazi population which is a distinct, isolated, and relatively homogenous genetic population derived from a limited number of founders; (3) linkage disequilibrium (LD) will have the power to identify genes with high and low genotypic relative risks; and (4) future analysis of gene interactions (epistasis) to identify the risks of specific sub-groups. Thus, by comparing the alleles at polymorphic loci throughout the human genome in men with and without prostate cancer from within a fairly homogenous, inbred population (i.e., Ashkenazi men) we hypothesize that we will be able to identify specific alleles associated with prostate cancer. To achieve this long range goal, the study is organized into three stages. Stage 1 includes recruitment of the initial study population and the search for candidate loci. Stage 2 involves testing candidate loci against a population-based control, and Stage 3 involves narrowing the genetic region to discover or test specific genes. A. Stage 1 1) To identify and recruit Ashkenazi men with hereditary prostate cancer. Two groups of men will be identified: a) Men with prostate cancer diagnosed before the age of 65 years and b) men with a family history of prostate cancer. These individuals and their affected family members will be recruited. 2) To identify and recruit Ashkenazi men without prostate cancer who are age-matched to the cases (by frequency rather than individually). They must be 55 years of age or above, have no history of a prostate biopsy, have an intact prostate gland, and have a normal PSA (i.e., prostate-specific antigen) blood test result from screenings. 3) To develop a detailed questionnaire instrument to collect data on family origins, family history, personal traits, and medical history. 4) To identify loci involved in the susceptibility to prostate cancer, blood will be collected for genetic analyses. PCR-based DNA polymorphic markers will be evaluated throughout the genome to test for linkage disequilibrium between the first 100 prostate cancer "cases" and the "controls". Candidate loci will be identified first by a 25 cM (i.e., centimorgan) genome scan. Differences in the frequency distribution of distinct alleles for each marker between the prostate cancer cases and the control group will be compared by statistical analyses. B. Stage 2 We will test for linkage disequilibrium in the next 100 cases and controls [against a population-based control] by progressing to a 10 cM scan based on the initial results from Stage 1. The prediction is that a gene involved in susceptibility to prostate cancer would show reduced linkage disequilibrium in the control population. Confirmation of such loci will be made and, in addition, specific genes and chromosomal regions implicated in prostate cancer will be evaluated. C. Stage 3 Regions showing significant disequilibrium will be further evaluated by additional markers and examination for common haplotypes. Recruitment of family members and affected-sib pairs in the cohorts will allow us not only define haplotypes, but to also test candidate regions by linkage analysis methods. In summary, at least 200 prostate cancer cases and 200 controls will be recruited in the first stage of this study. Questionnaire data and a blood sample will be obtained. DNA will be purified for polymorphic marker analyses. Marker analyses will be performed in a staged manner. Allele frequencies will be compared between the first 100 cases and controls by statistical methods to identify candidate loci in Stage 1. Candidate loci will be evaluated in the next 100 cases and controls. Future studies including haplotype analyses will be performed to narrow the genetic region.