Genetic Studies of Uterine Leiomyomata

子宫平滑肌瘤的遗传学研究

• 批准号: 7848517
• 负责人: Cynthia Casson Morton
• 金额: $ 37.83万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-20 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848517
• 关键词: Accounting; Affect; African American; Age; Anemia; Area; Benign; Biological; Biological Models; Biology; Blood Transfusion; Candidate Disease Gene; Caucasians; Caucasoid Race; Cell physiology; Chromosomal Rearrangement; Chromosome abnormality; Chromosomes, Human, Pair 10; Chromosomes, Human, Pair 12; Cytogenetics; Databases; Development; Diagnosis; Differentiated Gene; Etiology; Event; Failure; Female; Fibroid Tumor; Foundations; Fright; Future; Gene Expression; Gene Proteins; Genes; Genetic; Genotype; Goals; Growth; HMGA1 gene; HMGA2 gene; Hemorrhage; High Prevalence; Histology; Hour; Human; Hysterectomy; In Vitro; Infertility; Investigation; Karyotype; Knowledge; Lead; Location; Malignant - descriptor; Malignant Neoplasms; Menstruation; Molecular; Molecular Cytogenetics; Molecular Profiling; Monozygotic Twinning; Monozygotic twins; Myometrial; Natural History; Neoplasms; Pathogenesis; Patients; Pelvis; Phenotype; Predisposition; Premature Birth; Prevalence; Procedures; Public Health; Race; Research; Role; Series; Smooth Muscle; Spontaneous abortion; Subgroup; Symptoms; Time; Tissue Banking; Tissue Banks; Tissue Microarray; Twin Multiple Birth; United States; Untranslated Regions; Uterine Fibroids; Uterus; Variant; Woman; cell growth; chromosome 7q loss; disability; experience; gene discovery; health disparity; in vivo; interest; leiomyosarcoma; myometrium; neoplastic cell; novel strategies; positional cloning; public health relevance; reproductive; research study; tumor; tumorigenesis

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.

描述（由申请人提供）：子宫平滑肌瘤或肌瘤是女性最常见的盆腔肿瘤，至少发生在20- 25%的育龄妇女中。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使人衰弱的症状，包括月经过多和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200，000例手术。很有可能是遗传倾向发展肌瘤;他们在非洲裔美国人中的频率至少是白人女性的三倍（代表严重的健康差异），单卵双胞胎子宫切除术的双对相关性约为双卵双胞胎的两倍。尽管近年来在这一领域有了这些发现和增强的研究，但关于这种种族倾向和参与肌瘤发病机制的特定基因仍有很多东西有待了解。同样值得关注的是，由于其分子机制尚不清楚，肌瘤很少发展为恶性的子宫平滑肌肉瘤。因此，子宫平滑肌瘤可以作为研究区分良性和恶性肿瘤的遗传事件的重要模型系统。在纤维瘤中观察到一致的染色体畸变，表明这些肿瘤中涉及的基因的位置。一些细胞遗传学亚组已被确定，我们已经成功地使用位置候选基因的方法，在确定两个高迁移率蛋白基因，HMGA 2和HMGA 1，分别位于染色体12和6，参与子宫肌瘤的病理生物学，除了MYST 4，位于染色体10。 本申请的主要目的是进一步了解子宫肌瘤的生物学。实验的重点是继续开发和使用子宫平滑肌瘤组织库和数据库的基因发现，基因表达研究，基因型-表型相关性。各种分子和细胞遗传学的方法将被用于鉴定，分离和表征的基因参与子宫肌瘤的发病机制和病理生物学。肿瘤细胞的染色体重排将为定位克隆实验提供生物学标志。转录谱分析提供了一种强有力的方法来区分不同细胞遗传学亚群的肌瘤以及不同组织学的肌瘤与其正常平滑肌对应物、子宫肌层或其恶性对应物子宫平滑肌肉瘤的基因。最后，HMGA 2序列变异体的潜在作用将通过各种机制实验来探索，以评估它们在子宫平滑肌瘤中的作用。 公共卫生相关性：这项研究的重要性是进一步了解子宫肌瘤的生物学。子宫平滑肌瘤或肌瘤是女性最常见的盆腔肿瘤，至少发生在20-25%的育龄妇女中。子宫平滑肌瘤可以作为研究区分良性和恶性肿瘤的遗传事件的重要模型系统。更全面地了解子宫肌瘤的发病机制和病理生物学相关基因将为今后子宫肌瘤的诊断、管理和治疗提供基础。