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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD060530-01A1
Application #
7848517
Study Section
Special Emphasis Panel (ZRG1-EMNR-A (50))
Program Officer
Parrott, Estella C
Project Start
2010-07-20
Project End
2015-05-31
Budget Start
2010-07-20
Budget End
2011-05-31
Support Year
1
Fiscal Year
2010
Total Cost
$378,250
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Ordulu, Zehra (2016) Fibroids: Genotype and Phenotype. Clin Obstet Gynecol 59:25-9
Ordulu, Zehra; Nucci, Marisa R; Dal Cin, Paola et al. (2016) Intravenous leiomyomatosis: an unusual intermediate between benign and malignant uterine smooth muscle tumors. Mod Pathol 29:500-10
Gallagher, C Scott; Morton, Cynthia C (2016) Genetic Association Studies in Uterine Fibroids: Risk Alleles Presage the Path to Personalized Therapies. Semin Reprod Med 34:235-41
Stewart, Elizabeth A; Morton, Cynthia C (2015) Cutaneous and Uterine Leiomyomas. Mayo Clin Proc 90:990
Ordulu, Zehra; Wong, Kristen E; Currall, Benjamin B et al. (2014) Describing sequencing results of structural chromosome rearrangements with a suggested next-generation cytogenetic nomenclature. Am J Hum Genet 94:695-709
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Hodge, Jennelle C; Kim, Tae-Min; Dreyfuss, Jonathan M et al. (2012) Expression profiling of uterine leiomyomata cytogenetic subgroups reveals distinct signatures in matched myometrium: transcriptional profilingof the t(12;14) and evidence in support of predisposing genetic heterogeneity. Hum Mol Genet 21:2312-29
Ordulu, Zehra; Dal Cin, Paola; Chong, Wilson W S et al. (2010) Disseminated peritoneal leiomyomatosis after laparoscopic supracervical hysterectomy with characteristic molecular cytogenetic findings of uterine leiomyoma. Genes Chromosomes Cancer 49:1152-60
Hodge, Jennelle C; Park, Peter J; Dreyfuss, Jonathan M et al. (2009) Identifying the molecular signature of the interstitial deletion 7q subgroup of uterine leiomyomata using a paired analysis. Genes Chromosomes Cancer 48:865-85

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