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Joint Effect of HSD3B1 and HSD3B2 Genes Is Associated with Hereditary and Sporadic Prostate Cancer Susceptibility¹

Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157 [B-l. C., S. L. Z., G. A. H., A. T., E. R. B., D. A. M., J. X.]; University of Maryland School of Medicine, Baltimore, Maryland 21201 [B-l. C.]; Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287 [S. D. I., K. E. W., P. C. W., W. B. I.]; National Human Genome Research Institute, NIH, Bethesda, Maryland 20892 [J. D. C., J. M. T.]

3ß-hydroxysteroid dehydrogenases (HSD3Bs), encoded by the HSD3B gene family at 1p13, have long been hypothesized to have a major role in prostate cancer susceptibility. The recent reports of a prostate cancer linkage at 1p13 provided additional evidence that HSD3B genes may be prostate cancer susceptibility genes. To evaluate the possible role of HSD3B genes in prostate cancer, we screened a panel of DNA samples collected from 96 men with or without prostate cancer for sequence variants in the putative promoter region, exons, exon-intron junctions, and 3'-untranslated region of HSD3B1 and HSD3B2 genes by direct sequencing. Eleven single nucleotide polymorphisms (SNPs) were identified, four of which, including a missense change (B1-N367T), were informative. These four SNPs were further genotyped in a total of 159 hereditary prostate cancer probands, 245 sporadic prostate cancer cases, and 222 unaffected controls. Although a weak association between prostate cancer risk and a missense SNP (B1-N367T) was found, stronger evidence for association was found when the joint effect of the two genes was considered. Men with the variant genotypes at either B1-N367T or B2-c7519g had a significantly higher risk to develop prostate cancer, especially the hereditary type of prostate cancer. Most importantly, the subset of hereditary prostate cancer probands, whose families provided evidence for linkage at 1p13, predominantly contributed to the observed association. Additional studies are warranted to confirm these findings.

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