Finding Genes for Uterine Fibroids

寻找子宫肌瘤的基因

• 批准号: 6805750
• 负责人: Cynthia Casson Morton
• 金额: $ 40.6万
• 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/6805750
• 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)：子宫肌瘤(UL)，也被称为肌瘤，是女性最常见的盆腔肿瘤。尽管UL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衰弱的症状，包括月经过多、盆腔不适和生殖失败。UL的治疗选择有限，手术是治疗的主要手段。事实上，UL是最常见的子宫切除术适应症，在美国每年有超过20万例手术。尽管UL是激素依赖型肿瘤已被公认，但其生长发育情况仍有待进一步研究。令人信服的证据表明，发生UL的遗传易感性。这些肿瘤在黑人女性中的发生率至少是白人女性的三倍，而同卵双胞胎子宫切除的双胞胎相关性大约是异卵双胞胎的两倍。对家族聚集性的研究表明，与未受影响的先证者的亲属相比，受影响先证者的一级亲属罹患UL的风险增加2.5倍；按先证者(45岁)和亲属(小于或等于40岁)对病例进行分层后，这一优势比增加到5.7。大约25%-40%的UL是核型异常的，基于染色体重排的定位克隆方法已经鉴定出几个与肿瘤病理生物学有关的基因。对两种罕见的孟德尔疾病--里德综合征(MIM150800)和遗传性子宫肌瘤病和肾细胞癌(HLRCC，MIM605839)进行了基因连锁分析，前者的特征是UL合并多发性皮肤平滑肌瘤，后者是一种以子宫肌瘤和乳头状肾细胞癌为特征的癌症综合征。尽管有这些重要的发现，我们仍然对使数百万女性患上这些肿瘤的基因一无所知。在这一应用中的实验将集中在鉴定、分离和表征与UL发病相关的基因。具体地说，我们建议通过进行全基因组扫描来识别使女性易患上UL的基因(www.fiids.net：“寻找肌瘤的基因”)。最终，了解与UL形成有关的遗传途径可能会改善受影响女性的治疗选择，并改变高危人群的生活方式。