Finding Genes for Uterine Fibroids

寻找子宫肌瘤的基因

• 批准号: 7114920
• 负责人: Cynthia Casson Morton
• 金额: $ 36.81万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-26 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7114920
• 关键词: clinical research; environment; epidemiology; female; gene expression; genetic susceptibility; human subject; leiomyoma; neoplastic growth; questionnaires; uterus; women' s health

DESCRIPTION (provided by applicant): Uterine leiomyomata (UL), also called fibroids, are the most common pelvic tumors in females. Although benign neoplasms, UL constitute a major public health problem as 20-25% of affected women experience debilitating symptoms including excessive menstrual bleeding, pelvic discomfort, and reproductive failure. Medical treatment options for UL are limited, and surgery is the mainstay of therapy. In fact, UL are the most common indication for hysterectomy accounting for over 200,000 procedures annually in the United States. Although it is well recognized that UL are steroid-dependent tumors, much remains to be known about their growth and development. Compelling evidence suggests a genetic liability to develop UL. These tumors are at least three times more frequent in black than in white women, and twin-pair correlations for hysterectomy in monozygotic twins are about twice that observed in dizygous twins. Studies of familial aggregation indicate a 2.5-fold increased risk for UL among first-degree relatives of affected probands compared to relatives of unaffected probands; this odds ratio increases to 5.7 after stratifying cases by age of proband (< 45 years) and of relatives (less than or equal to 40 years). About 25-40% of UL are karyotypically abnormal, and several genes involved in the pathobiology of the tumors have been identified using positional cloning approaches based on chromosome rearrangements. Genetic linkage analysis in two rare Mendelian disorders, Reed syndrome (MIM150800), characterized by UL in association with multiple cutaneous leiomyomata, and hereditary leiomyomatosis and renal cell cancer (HLRCC, MIM605839), a cancer syndrome characterized by uterine leiomyomas and papillary renal cell carcinoma, resulted in the surprising finding of mutations in the gene for fumarate hydratase. Despite these important findings, we remain ignorant of the genes that predispose millions of women to develop these tumors. Experiments in this application will focus on identification, isolation and characterization of genes involved in the pathogenesis of UL. Specifically, we propose to identify genes that predispose women to develop UL by performing a genome-wide scan (www.fibroids.net: "Finding Genes for Fibroids"). Ultimately, understanding genetic pathways involved in the formation of UL may lead to I improved treatment options for affected women and lifestyle changes for at risk individuals.

描述（申请人提供）：子宫平滑肌瘤（UL），又称肌瘤，是女性最常见的盆腔肿瘤。虽然是良性肿瘤，但UL构成了一个主要的公共卫生问题，因为20-25%的受影响妇女会出现虚弱的症状，包括月经过多出血、盆腔不适和生殖功能衰竭。UL的医疗选择是有限的，手术是主要的治疗方法。事实上，UL是子宫切除术最常见的指征，在美国每年有超过20万例手术。虽然众所周知，UL是类固醇依赖性肿瘤，但其生长和发展仍有待了解。令人信服的证据表明，遗传倾向于发展UL。这些肿瘤在黑人妇女中的发生率至少是白人妇女的三倍，而在同卵双胞胎中子宫切除术的双胞胎相关性约为异卵双胞胎的两倍。家族聚集研究表明，与未受影响先证的亲属相比，受影响先证的一级亲属患UL的风险增加2.5倍；按先证者年龄（< 45岁）和亲属年龄（小于或等于40岁）对病例进行分层后，这一比值比增加到5.7。大约25-40%的肿瘤核型异常，一些参与肿瘤病理生物学的基因已经通过基于染色体重排的定位克隆方法被鉴定出来。对两种罕见孟德尔疾病——以UL与多发性皮肤平滑肌瘤相关为特征的Reed综合征（MIM150800），以及以子宫平滑肌瘤和乳头状肾细胞癌为特征的遗传性平滑肌瘤病和肾细胞癌（HLRCC, MIM605839）——的遗传连锁分析，令人惊讶地发现富马酸水合酶基因突变。尽管有这些重要的发现，我们仍然不知道是什么基因使数百万女性容易患上这些肿瘤。本应用的实验将集中于鉴别、分离和表征参与UL发病机制的基因。具体地说，我们建议通过全基因组扫描（www.fibroids.net：“寻找肌瘤基因”）来确定使女性易患子宫肌瘤的基因。最终，了解参与UL形成的遗传途径可能会改善受影响妇女的治疗方案，并改变高危个体的生活方式。