Finding Genes for Uterine Fibroids

寻找子宫肌瘤的基因

• 批准号: 6740757
• 负责人: Cynthia Casson Morton
• 金额: $ 40.26万
• 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/6740757
• 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（UL），也称为肌瘤，是女性最常见的骨盆肿瘤。尽管良性肿瘤构成了良性的肿瘤，但构成了一个重大的公共卫生问题，因为20-25％的受影响妇女经历了使人衰弱的症状，包括过度的月经出血，骨盆不适和生殖失败。 UL的医疗选择有限，手术是治疗的主要手段。实际上，在美国，UL是子宫切除术每年超过200,000个程序的最常见迹象。尽管众所周知，UL是类固醇依赖性肿瘤，但对其生长和发育尚待了解。令人信服的证据表明，发展UL的遗传责任。这些肿瘤在黑色中的频率至少是白人女性的三倍，并且单卵双胞胎的子宫切除术的双对相关性大约是在双胞胎双胞胎中观察到的两倍。对家族聚集的研究表明，与未受影响的概率的亲属相比，受影响的概率的一级亲属中UL的风险增加了2.5倍。根据概率年龄（<45岁）和亲戚（小于或等于40年）将病例分层后，该赔率比增加到5.7。大约25-40％的UL在核型上异常，并且已经使用基于染色体重排的位置克隆方法鉴定出参与肿瘤病理生物学的几个基因。在两种罕见的门德尔疾病（MIM150800）中进行的遗传连锁分析，其特征在于与多个皮肤平滑肌瘤以及遗传性平滑肌瘤病和肾细胞癌（HLRCC，MIM605839）相关的特征富马酸水合物的基因。尽管有这些重要的发现，但我们仍然不知道易患数百万妇女发展这些肿瘤的基因。该应用程序中的实验将集中于识别，分离和表征UL发病机理所涉及的基因。具体而言，我们建议通过进行全基因组扫描来识别易感女性发展UL的基因（www.fibroids.net：“为肌瘤寻找基因”）。最终，了解UL形成所涉及的遗传途径可能会导致我改善受影响妇女的治疗选择，并改变风险个人的生活方式。