The Progesterone Receptor Gene and Ovarian Cancer Risk

描述(由申请人提供)： 根据实验和流行病学观察，孕激素受体基因(PGR)是侵袭性上皮性卵巢癌(卵巢癌)易感性的有力候选基因。孕酮对卵巢肿瘤细胞的增殖有很强的抑制作用，与正常卵巢表面上皮细胞相比，卵巢肿瘤细胞中孕酮受体(PR)的表达下调。此外，PR阳性的肿瘤与改善预后有关，在卵巢肿瘤中经常观察到PGR基因杂合性丢失。怀孕和口服避孕药(OC)的使用都代表着较高的孕酮水平，对卵巢癌具有保护作用。 我们在过去十年在洛杉矶县进行的两项病例对照研究中表明，PGR基因rs608995的单核苷酸多态(SNP)及其所在的两种单倍型与卵巢癌风险增加约3倍相关。这项申请旨在缩小PGR的90kb基因组区域，该区域含有卵巢癌易感等位基因(S)。缩小该区域范围的这一重要步骤将有助于指导可能识别因果等位基因(S)的功能研究，并可能导致预防和治疗干预。 为了实现这一目标，我们建议在健康女性的多种族基因特征小组中对更多的SNPs进行基因分型，并在卵巢癌病例和对照中进行SNP发现，以完善风险区域的连锁不平衡(BLOCK)结构。在研究了新改进的风险区域的单倍型多样性后，我们将在一个新的病例对照研究样本中确定描述这种多样性所需的SNPs，并对它们进行基因分型，样本包括338例病例和380名对照。我们还将测试我们之前的两项病例对照研究，以确定是否存在任何额外的SNPs，包括326个病例和493个对照(许多SNPs已经在这些人群中进行了测试)。

DESCRIPTION (provided by applicant): 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).