Genetic Studies of Uterine Leiomyomata

描述(申请人提供)：子宫肌瘤，或肌瘤，是最常见的女性盆腔肿瘤，至少发生在20-25%的育龄妇女。虽然是良性肿瘤，但它们构成了一个主要的公共卫生问题，因为25%-50%的受影响妇女会出现虚弱的症状，包括月经过多、盆腔不适以及生殖失败。子宫肌瘤是子宫切除术的主要适应症，在美国每年有超过20万例子宫切除术。极有可能存在患子宫肌瘤的遗传倾向；在非裔美国人中，子宫瘤的发生率至少是高加索女性的三倍(这代表着严重的健康差距)，而同卵双胞胎子宫切除的双胞胎相关性大约是眩晕双胞胎的两倍。尽管有这些发现和近年来在这一领域加强的研究，但关于这种种族易感性和参与肌瘤发病机制的特定基因仍有许多有待了解。同样令人特别感兴趣和分子机制不明的是，子宫肌瘤很少发展为与其恶性对应的子宫平滑肌肉瘤。因此，子宫肌瘤可以作为一个重要的模型系统来研究区分良、恶性肿瘤的遗传事件。在肌瘤中观察到了一致的染色体异常，表明了与这些肿瘤有关的基因的位置。一些细胞遗传学亚群已经被确定，我们已经成功地利用位置候选基因方法确定了两个高迁移率蛋白基因HMGA2和HMGA1，分别位于第12和6号染色体，除了位于第10染色体的MYST4外，还参与了子宫肌瘤的病理生物学。这一拟议应用的主要目的是加深我们对子宫肌瘤生物学的理解。实验的重点是继续开发和使用子宫肌瘤组织库和数据库，用于基因发现、基因表达研究和基因-表型相关性。各种分子和细胞遗传学方法将被用于鉴定、分离和鉴定与子宫肌瘤发病机制和病理生物学有关的基因。肿瘤细胞中的染色体重排将为定位克隆实验提供生物标志。转录图谱提供了一种有效的方法来区分不同细胞遗传学亚型的肌瘤和不同组织结构的肌瘤与正常的平滑肌对应的子宫肌层或恶性的子宫肌肉肉瘤。最后，将通过各种机制实验来探索HMGA2中序列变异的潜在作用，以评估它们在子宫肌瘤中的作用。 公共卫生相关性：这项研究的重要性是加深我们对子宫肌瘤生物学的理解。子宫肌瘤或肌瘤是女性最常见的盆腔肿瘤，至少有20%-25%的育龄妇女会发生。子宫肌瘤可以作为一个重要的模型系统来研究区分良、恶性肿瘤的遗传事件。更全面地了解子宫肌瘤的发病机制和病理生物学过程中涉及的基因将为今后子宫肌瘤的诊断、治疗和治疗提供基础。

DESCRIPTION (provided by applicant): Uterine leiomyomata, or fibroids, are the most common pelvic tumors in females and occur in a minimum of 20- 25% of women of reproductive age. Although benign neoplasms, they constitute a major public health problem as 25-50% of affected women experience debilitating symptoms including excessive menstrual bleeding and pelvic discomfort as well as reproductive failure. Fibroids are the major indication for hysterectomy accounting for over 200,000 procedures annually in the United States. It is highly likely that there is a genetic liability to develop fibroids; they are at least three times more frequent in African American than Caucasian women (representing a serious health disparity) and twin-pair correlations for hysterectomy in monozygotic twins are about twice that observed in dizygous twins. Despite these findings and enhanced research in this area in recent years, much remains to be known about this racial predisposition and specific genes involved in the pathogenesis of fibroids. Also of particular interest and of unknown molecular mechanism, fibroids rarely proceed to their malignant counterpart, uterine leiomyosarcoma. Thus, it follows that uterine leiomyomata may serve as an important model system to study the genetic events that distinguish benign and malignant neoplasms. Consistent chromosome aberrations have been observed in fibroids indicating the location of genes involved in these tumors. A number of cytogenetic subgroups have been identified and we have been successful in using positional candidate gene approaches in determining that two high mobility protein genes, HMGA2 and HMGA1, located on chromosomes 12 and 6, respectively, participate in the pathobiology of uterine leiomyomata, in addition to MYST4, located on chromosome 10. The major goal of this proposed application is to further our understanding of the biology of uterine leiomyomata. Experiments are focused on continuing to develop and use a uterine leiomyomata tissue bank and database for gene discovery, gene expression studies, and genotype-phenotype correlations. A variety of molecular and cytogenetic approaches will be used in the identification, isolation and characterization of genes involved in the pathogenesis and pathobiology of uterine leiomyomata. Chromosomal rearrangements in tumor cells will provide biological landmarks for positional cloning experiments. Transcriptional profiling offers a powerful approach to discriminate genes that differentiate fibroids of different cytogenetic subgroups as well as fibroids of variant histologies from their normal smooth muscle counterpart, the myometrium, or their malignant counterpart, uterine leiomyosarcoma. Lastly, the potential role of sequence variants in HMGA2 will be explored by a variety of mechanistic experiments to assess their role in uterine leiomyomata. PUBLIC HEALTH RELEVANCE: The importance of this research is to further our understanding of the biology of uterine leiomyomata. Uterine leiomyomata, or fibroids, are the most common pelvic tumors in females and occur in a minimum of 20-25% of women of reproductive age. Uterine leiomyomata may serve as an important model system to study the genetic events that distinguish benign and malignant neoplasms. A more complete understanding of the genes involved in the pathogenesis and pathobiology of uterine leiomyomata will provide a foundation for future diagnosis, management and treatment of uterine fibroids.