Uterine leiomyomata, or fibroids, are the most common pelvic tumors in females and occur in 20-25 percent of women of reproductive age. Although benign neoplasms, they constitute a major health problem as 25-50 percent of affected women experience debilitating symptoms including excessive menstrual bleeding and pelvic discomfort as well as reproductivefailure. 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 uterine leiomyomata; these tumors are at least three times more frequent in Black than Caucasian women and the twin pair correlations for hysterectomy in monozygotic twins are about twice that observed in dizygous twins. Despite these findings, relatively little is known about this racial predisposition or specific genes involved in the pathogenesis of fibroids. Also of particular interest is the observation that these tumors rarely; if ever, proceed to their malignant counterparts. Uterine leiomyomata may serve as an important model system to study the genetic events which distinguish benign and malignant neoplasms. Consistent chromosome aberrations have been observed in fibroids indicating the location of genes involved in these tumors. At least six cytogenetic subgroups have been identified and we have been successful in using positional candidate gene approaches in determining that two high mobility protein genes, HMGIC and HMGlY, located on chromosomes 12 and 6, respectively participate in the pathobiology of uterine leiomyomata. The major goal of this proposed renewal applicaiton is to further our understanding of the biology of uterine leiomyomata. We will use molecular and cytogenetic studies to characterize further the expression and mechanism of the two high mobility group protein genes, HMGiC and HMGlY. Additional experiments will be focused on the identification, isolation and characterization of othe genes involved in the pathogenesis and pathobiology of uterine leiomyomata. Two positional cloning projects already underway are focused on genes consistently involved in rearrangements in these tumors. Identification and molecular characterization of genes at these sites will contribute to understianding the role of these genes in normal cellular processes, and may facilitate developments in the clinical management of leiomyomate and other solid tumors.
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