This study aims to determine genetic risk factors in families with human prostate cancer. Papers published previously have shown evidence of prostate cancer susceptibility genes in regions of chromosomes 1, 8 and X. These results have been followed up by intensive linkage analyses of additional families to markers in these regions and in other regions that showed some mild evidence of linkage in the initial genome scan. Families have been obtained and genotyped from several regions of the United States, Finland, Iceland and Sweden. Dr. Bailey-Wilson's group is involved in the analyses of the Finnish and Icelandic data and the African-American data. Papers were previously published in Clinical Cancer Research (2000) showing strong evidence for the chromosome X locus but limited evidence for the chromosome 1 locus in our Finnish data. Another paper was published in Human Genetics (2000) detailing the linkage results in the Icelandic data. Efforts are underway to develop additional family resources for this project. These investigators have joined the International Prostate Cancer Genetics Consortium (ICPCG) to try to localize prostate cancer loci more rapidly, and a meta-analysis paper from this consortium describing the evidence for linkage to the chromosome 1 locus in a very large combined dataset was published previously. Previously, our group identified mutations in the ribonuclease-L (RNASEL) gene as being the locus in our chromosome 1 linkage region causing increased risk to prostate cancer. We also found evidence that mutations in the macrophage scavenger receptor 1 gene plays a role in prostate cancer risk. Several papers have been published with these results. We also published the results of segregation analyses of breast and prostate cancer. The ICPCG consortium is currently performing meta-analyses of two other regions that have been implicated as regions of susceptibility loci in prostate cancer. Dr. Bailey-Wilson is in charge of the Chromosome X meta-analysis. This work is ongoing. Association analyses have also been performed on additional marker data from Finland, Iceland and the U.S. A linkage genome-wide scan of families from Finland, Sweden, and the U.S., including a significant number of African-American families from the African American Hereditary Prostate Cancer Consortium, of which Dr. Bailey-Wilson is a member, is ongoing in this fiscal year and will continue into the next year. A paper detailing the results of this genome wide scan in the Finnish families and another with results of a metaanalysis of several of these datasets have been published in this fiscal year. Fine mapping markers have been genotyped for the Finnish dataset and a manuscript presenting strong evidence for a locus on chromosome 3p is in press. We will continue to pursue evidence of a major locus in this region in these families. A new set of 43 extended Finnish prostate cancer pedigrees have been collected, power studies have been performed and genotyping for a genome wide scan has been started. Analyses will be performed in the next fiscal year.
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