Finding Genes for Uterine Fibroids

描述（由申请人提供）：子宫平滑肌瘤（UL），也称为纤维瘤，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使人衰弱的症状，包括月经过多、盆腔不适和生殖失败。UL的医学治疗选择有限，手术是治疗的主要手段。事实上，UL是子宫切除术的最常见适应症，在美国每年有超过200，000例手术。虽然它是公认的UL是类固醇依赖性肿瘤，仍有很多关于他们的生长和发展的了解。令人信服的证据表明，遗传倾向于发展UL。这些肿瘤在黑人女性中的发生率至少是在白色女性中的三倍，并且在同卵双胞胎中子宫切除术的双对相关性大约是在双卵双胞胎中观察到的两倍。家族聚集性研究表明，与未受影响的先证者的亲属相比，受影响的先证者的一级亲属中UL的风险增加2.5倍;在按先证者（< 45岁）和亲属（小于或等于40岁）的年龄对病例进行分层后，该比值比增加至5.7。大约25-40%的UL是核型异常的，并且已经使用基于染色体重排的位置克隆方法鉴定了涉及肿瘤病理生物学的几个基因。两种罕见的孟德尔疾病的遗传连锁分析，里德综合征（MIM 150800），其特征在于UL与多发性皮肤平滑肌瘤，和遗传性平滑肌瘤病和肾细胞癌（HLRCC，MIM 605839），一种癌症综合征，其特征在于子宫平滑肌瘤和乳头状肾细胞癌，导致在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，我们仍然不知道使数百万妇女易患这些肿瘤的基因。本申请中的实验将集中于鉴定、分离和表征参与UL发病机制的基因。具体来说，我们建议通过进行全基因组扫描来识别使女性易患UL的基因（www.fibroids.net：“寻找纤维瘤基因”）。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选择，并改变高危人群的生活方式。

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.