Finding Genes for Uterine Fibroids

寻找子宫肌瘤的基因

• 批准号: 6930329
• 负责人: Cynthia Casson Morton
• 金额: $ 37.86万
• 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/6930329
• 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（由申请人提供）：子宫平滑肌瘤（UL），也称为肌瘤，是女性最常见的盆腔肿瘤。虽然 UL 是良性肿瘤，但它构成了一个主要的公共健康问题，因为 20-25% 的受影响女性会出现衰弱症状，包括月经出血过多、盆腔不适和生殖障碍。 UL 的治疗选择有限，手术是主要治疗方法。事实上，UL 是子宫切除术最常见的适应症，在美国每年有超过 200,000 例手术。尽管人们普遍认为 UL 是类固醇依赖性肿瘤，但关于其生长和发展仍有许多未知之处。令人信服的证据表明，患有 UL 具有遗传倾向。这些肿瘤在黑人女性中的发病率至少是白人女性的三倍，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中观察到的两倍。家族聚集性研究表明，与未患病先证者的亲属相比，患病先证者的一级亲属患 UL 的风险增加 2.5 倍；按先证者年龄（< 45 岁）和亲属（小于或等于 40 岁）对病例进行分层后，这一比值比增加至 5.7。大约 25-40% 的 UL 存在核型异常，并且使用基于染色体重排的定位克隆方法已鉴定出与肿瘤病理学有关的几个基因。两种罕见的孟德尔疾病的遗传连锁分析，即里德综合征 (MIM150800)，其特征是 UL 与多发性皮肤平滑肌瘤相关，以及遗传性平滑肌瘤病和肾细胞癌 (HLRCC，MIM605839)，这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，导致了富马酸水合酶基因突变的惊人发现。尽管有这些重要的发现，我们仍然对导致数百万女性罹患这些肿瘤的基因一无所知。本申请中的实验将重点关注与 UL 发病机制相关的基因的识别、分离和表征。具体来说，我们建议通过进行全基因组扫描来识别女性易患 UL 的基因（www.fibroids.net：“Finding Genes for Fibroid”）。最终，了解 UL 形成所涉及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。