The Progesterone Receptor Gene and Ovarian Cancer Risk

黄体酮受体基因与卵巢癌风险

• 批准号: 6889385
• 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
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-22 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6889385
• 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' s health

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）是一个强有力的候选基因的侵袭性上皮性卵巢癌（卵巢癌）的易感性的基础上的实验和流行病学观察。孕激素对卵巢肿瘤细胞的增殖有很强的抑制作用，并且相对于正常卵巢表面上皮细胞，卵巢肿瘤细胞中孕激素受体（PR）的表达下调。此外，PR阳性肿瘤与预后改善相关，在卵巢肿瘤中观察到PGR基因座杂合性丢失频繁。怀孕和口服避孕药（OC）的使用，这代表了较高的孕酮状态，对卵巢癌有保护作用。 在过去的十年中，我们在洛杉矶县进行的两项病例对照研究中发现，PGR中的一个单核苷酸多态性（SNP）rs608995及其所在的两个单倍型与卵巢癌风险增加约3倍相关。本申请寻求缩小携带卵巢癌易感性等位基因的PGR的90kb基因组区域。缩小该区域的这一重要步骤将有助于指导功能研究，这些研究可以确定致病等位基因，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组中进行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，并在包括338例病例和380例对照的新病例对照研究样本中对其进行基因分型。我们还将测试我们之前的两项病例对照研究中任何其他确定的SNP，包括326例病例和493例对照（许多SNP已经在这些人群中进行了测试）。