The progesterone receptor gene (PGR) is a strong candidate gene for invasive epithelial ovarian cancer (ovarian cancer) susceptibility based on both experimental and epidemiologic observations. Progesterone shows a strong inhibitory effect on ovarian tumor cell proliferation and progesterone receptor (PR) expression is down regulated in ovarian tumor cells relative to normal ovarian surface epithelial cells. Also, PR-positive tumors are associated with improved prognosis and frequent loss of heterozygosity at the PGR locus is observed in ovarian tumors. Both pregnancy and oral contraceptive (OC) use, which represent states of higher progesterone, are protective against ovarian cancer. We have shown that a single nucleotide polymorphism (SNP) in the PGR, rs608995, and the two haplotypes on which it resides, is associated with an approximately 3-fold increased risk of ovarian cancer in two case-control studies conducted in Los Angeles County over the past decade. This application seeks to narrow down the 90 kb genomic region of the PGR which harbors an ovarian cancer susceptibility allele(s). This important step of narrowing down this region will help guide functional studies that could identify the causal allele(s) and possibly lead to preventive and therapeutic interventions. To accomplish this objective we are proposing to genotype additional SNPs in a multiethnic gene characterization panel of healthy women and to conduct SNP discovery among ovarian cancer cases and controls to refine the linkage disequilibrium (block) structure of the risk region. After examining the haplotypic diversity of the newly refined risk region, we will identify the SNPs required to describe the diversity and genotype them in a new case-control study sample including 338 cases and 380 controls. We will also test our previous two case-control studies for any additional identified SNPs, including 326 cases and 493 controls (many of the SNPs have already been tested in these populations).
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