The Progesterone Receptor Gene and Ovarian Cancer Risk

黄体酮受体基因与卵巢癌风险

基本信息

批准号：
6951379
负责人：
CELESTE Leigh PEARCE
金额：
$ 8.13万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-22 至 2007-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6951379
关键词：
cancer risk capillary electrophoresis clinical research computer program /software gene expression genotype human genetic material tag linkage disequilibriums mass spectrometry matrix assisted laser desorption ionization neoplasm /cancer genetics ovary neoplasms polymerase chain reaction progesterone receptors receptor expression single nucleotide polymorphism women&apos s health

项目摘要

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).

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）易感性的强候选基因。黄体酮对卵巢肿瘤细胞增殖有很强的抑制作用，相对于正常卵巢表面上皮细胞，卵巢肿瘤细胞中黄体酮受体（PR）的表达下调。此外，PR 阳性肿瘤与预后改善相关，并且在卵巢肿瘤中观察到 PGR 基因座杂合性频繁丢失。怀孕和使用口服避孕药（OC）代表较高的孕激素状态，都可以预防卵巢癌。我们在洛杉矶县进行的两项病例对照研究表明，PGR rs608995 中的单核苷酸多态性 (SNP) 及其所在的两个单倍型与卵巢癌风险增加约 3 倍相关过去十年。本申请旨在缩小包含卵巢癌易感等位基因的 PGR 90 kb 基因组区域的范围。缩小该区域范围的这一重要步骤将有助于指导功能研究，从而识别因果等位基因，并可能导致预防和治疗干预措施。为了实现这一目标，我们建议在健康女性的多种族基因表征小组中对额外的 SNP 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（区块）结构。在检查新细化的风险区域的单倍型多样性后，我们将确定描述多样性所需的 SNP，并在新的病例对照研究样本（包括 338 个病例和 380 个对照）中对它们进行基因分型。我们还将测试我们之前的两项病例对照研究中是否有任何其他已识别的 SNP，包括 326 个病例和 493 个对照（许多 SNP 已在这些人群中进行了测试）。