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）：孕激素受体基因（PGR）是基于实验和流行病学观察的侵入性上皮卵巢癌（卵巢癌）易感性的强大候选基因。孕酮对卵巢肿瘤受体（PR）的表达对卵巢肿瘤细胞的调节表现出强烈的抑制作用，相对于正常的卵巢表面上皮细胞。同样，在卵巢肿瘤中观察到PGR基因座的预后改善和杂合性频繁丧失有关。代表孕酮较高状态的妊娠和口服避孕药（OC）使用均针对卵巢癌。我们已经表明，PGR中的单个核苷酸多态性（SNP）rs608995和其所在的两种单倍型与过去十年在洛杉矶县进行的两种病例对照研究中的卵巢癌风险增加了约3倍。该应用程序旨在缩小PGR的90 KB基因组区域，该区域具有卵巢癌易感性等位基因。缩小该区域的这一重要步骤将有助于指导可以识别因果等位基因的功能研究，并可能导致预防和治疗性干预措施。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基因型额外的SNP，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（块）结构。在检查了新精致的风险区域的单倍型多样性之后，我们将在新的病例对照研究样本中确定描述多样性和基因型所需的SNP，包括338例病例和380例对照。我们还将针对任何其他确定的SNP进行测试我们的前两个病例对照研究，包括326例病例和493个对照（许多SNP已经在这些人群中进行了测试）。