Genetic Studies of Uterine Leiomyomata

子宫平滑肌瘤的遗传学研究

• 批准号: 8300035
• 负责人: Cynthia Casson Morton
• 金额: $ 34.56万
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300035
• 关键词: 5' Untranslated Regions; 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; 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.

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，至少有 20-25% 的育龄女性患有该肿瘤。虽然它们是良性肿瘤，但它们构成了一个主要的公共卫生问题，因为 25-50% 受影响的女性会出现衰弱症状，包括月经出血过多、盆腔不适以及生殖障碍。肌瘤是子宫切除术的主要适应症，在美国每年进行超过 200,000 例手术。很可能存在罹患肌瘤的遗传倾向；非裔美国人的子宫切除率至少是白人女性的三倍（代表着严重的健康差异），同卵双胞胎中子宫切除术的双胞胎相关性大约是异卵双胞胎中观察到的两倍。尽管近年来在这一领域取得了这些发现和加强的研究，但对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了解。同样令人感兴趣且分子机制未知的是，肌瘤很少发展为恶性对应物子宫平滑肌肉瘤。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。在肌瘤中观察到一致的染色体畸变，表明这些肿瘤涉及的基因的位置。已经鉴定了许多细胞遗传学亚组，并且我们已经成功地使用位置候选基因方法确定了分别位于 12 号和 6 号染色体上的两个高迁移率蛋白基因 HMGA2 和 HMGA1，参与子宫平滑肌瘤的病理学。除了位于 10 号染色体上的 MYST4 之外。这项拟议应用的主要目标是进一步了解子宫平滑肌瘤的生物学。实验重点是继续开发和使用子宫平滑肌瘤组织库和数据库进行基因发现、基因表达研究和基因型-表型相关性。多种分子和细胞遗传学方法将用于鉴定、分离和表征与子宫平滑肌瘤发病机制和病理学有关的基因。肿瘤细胞中的染色体重排将为定位克隆实验提供生物学标志。转录谱提供了一种强有力的方法来区分不同细胞遗传学亚组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）或恶性对应物（子宫平滑肌肉瘤）的基因。最后，将通过各种机制实验探索 HMGA2 中序列变异的潜在作用，以评估其在子宫肌瘤中的作用。