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The Genetic Bases of Uterine Fibroids; a Review

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The Genetic Bases of Uterine Fibroids; a Review Review Article The Genetic Bases of Uterine Fibroids; A Review Veronica Medikare 1, Lakshmi Rao Kandukuri 2, Venkateshwari Ananthapur 3, Mamata Deenadayal 4, Pratibha Nallari 1* 1- Department of Genetics, Osmania University, Hyderabad, India 2- Center for Cellular and Molecular Biology, Habsiguda, Hyderabad, India 3- Institute of Genetics and Hospital for Genetic Diseases, Begumpet, Hyderabad, India 4- Infertility Institute and research Center, Secunderabad, India Abstract Uterine leiomyomas/fibroids are the most common pelvic tumors of the female genital tract. The initiators remaining unknown, estrogens and progesterone are considered as promoters of fibroid growth. Fibroids are monoclonal tumors showing 40-50% karyo- typically detectable chromosomal abnormalities. Cytogenetic aberrations involving chromosomes 6, 7, 12 and 14 constitute the major chromosome abnormalities seen in leiomyomata. This has led to the discovery that disruptions or dysregulations of HMGIC and HMGIY genes contribute to the development of these tumors. Genes such as RAD51L1 act as translocation partners to HMGIC and lead to disruption of gene structure leading to the pathogenesis of uterine fibroids. The mechanism underlying * Corresponding Author: this disease is yet to be identified. The occurrence of PCOLCE amid a cluster of at Downloaded from http://www.jri.ir Pratibha Nallari, Department of Genetics, least eight Alu sequences is potentially relevant to the possible involvement of Osmania University, PCOLCE in the 7q22 rearrangements that occur in many leiomyomata. PCOLCE is Hyderabad, 500 007, implicated in cell growth processes. Involvement of Alu sequences in rearrangements India can lead to the disruption of this gene and, hence, loss of control for gene expression E-mail: leading to uncontrolled cell growth. This can also lead to the formation of fibroids. [email protected] Though, cytogenetics provides a broad perspective on uterine fibroid formation, Received: Mar. 19, 2011 further molecular analysis is required to understand the etiopathogenesis of uterine Accepted: Jun. 28, 2011 fibroids. Keywords: Chromosomal translocation, Chromosomal, Estrogen, Gene rearrangement, Progesterone, Uterine fibroids, Uterine Leiomyomas (UL). To cite this article: Medikare V, Kandukuri LR, Ananthapur V, Deenadayal M, Nallari P. The Genetic Bases of Uterine Fibroids; A Review. J Reprod Infertil. 2011;12(3):181-191. Introduction terine leiomyomas (UL), commonly known as are usually detected in women in their 30's and fibroids, are non-cancerous tumors arising 40's and shrink after menopause in the absence of from the myometrium (smooth muscle layer) of post-menopausal estrogen replacement therapy the uterus. In addition to smooth muscle, leiomy- (1). omas are also composed of extracellular matrix Leiomyomas arise from the overgrowth of (i.e., collagen, proteoglycan, fibronectin). Leio- smooth muscle and connective tissue in the uterus myomas are the most common solid pelvic tumor (2). There are two components to myoma devel- in women, causing symptoms in approximately opment; first the transformation of normal myo- 25% of women of reproductive age. However, cytes to abnormal myocytes and their growth into with careful pathologic inspection of the uterus, clinically apparent tumors. Apart from their tu- the overall prevalence of leiomyomas increases to morigenic potential, they are morphologically over 70%, because leiomyomas can be present similar at the cellular level to normal myometrial without symptoms in many women. Leiomyomas smooth-muscle cells (MSMCs). Leiomyomas may J Reprod Infertil. 2011;12(3):181-191 JRI Uterine Leiomyomas have single or multiple mutated smooth-muscle pain, urinary incontinence, and constipation. Leio- tumor nodules of varying size attached and/or myomas may lead to infertility, spontaneous abor- within the myometrium that are encircled by tions, premature labor, or dystocia. Progression of varying amounts of extracellular fibrous connect- leiomyoma to malignant leiomyosarcoma (LMS) ive tissue. Microscopic determinations reveal they is very rare (6). have interlacing bundles of spindle-shaped or The present review focusses on the cytogenetic stellate smooth-muscle cells with little cellular and molecular aspects which contribute to the pleomorphism or mitotic activity (3). pathogenesis of uterine leiomyomas. Here the The identity of the factor(s) and molecular genetics of leiomyomata and the current under- mechanisms involved in the cellular transforma- standing of cytogenetic abberations and gene ex- tion of myometrial cells into leiomyoma remains pression with respect to their contributions to the unknown. Evidence also exists supporting the development of these tumors is summarized. involvement of genomic instability influencing Risk factors: Risk factors are characteristics genes such as estrogen and progesterone recep- associated with a condition generally identified by tors. Several genomic and proteomic studies have epidemiological studies. There is a suggestion of also provided evidence for altered molecular slightly increased risk of fibroids associated with environment of leiomyomas compared to the nor- early menarche (7 - 9). The early onset of men- mal myometrium, as a possible biomarker in their strual cycles may increase the number of cell proliferation and regression (4). divisions that the myometrium undergoes during Global gene expression profiling of uterine the reproductive years, resulting in an increased Downloaded from http://www.jri.ir leiomyomas (ULMs) revealed that hundreds of risk for mutations in gene/s controlling myome- genes were dysregulated including those with trial proliferation (10, 11). functional roles in cell proliferation, differenti- An increase in age has been demonstrated to ation and extracellular matrix production. So far, increase the prevalence of fibroids during the only a few specific genes or cytogenetic aberra- reproductive years (12). Hormonal factors associ- tions have been identified to be associated with ated with pre-menopause may be important ULMs. While many of the dysregulated genes modulators for the development of fibroids during may function as either effectors or promoters of late reproductive years; alternatively this may also ULMs growth, they are likely to be secondarily be due to the cumulative culmination of 20-30 induced and indirectly responsible for tumor years of stimulation by estrogen and progesterone. growth into morbid and symptomatic ULMs (5). The other factors involved are menopause, obes- Classification of leiomyomas: Leiomyomas are ity, diet, exercise, racial differences, geographic classified by their location in the uterus. Sub- differences, oral contraceptives, hormone replace- serosal leiomyomas are located just under the ment theory, etc (13). uterine serosa and may be pedunculated (attached Apart from these, hyperinsulinemia is con- to the corpus by a narrow stalk) or sessile (broad- sidered as a risk factor since insulin may influence based). Intramural leiomyomas are found predom- UL development through direct promotion of inantly within the thickness of myometrium but myometrial smooth muscle cell proliferation or by may distort the uterine cavity or cause an irregular increasing circulating levels of ovarian hormones external uterine contour. Submucous leiomyomas (14). are located just under the uterine mucosa (endo- Theories of fibroid formation: Despite the major metrium) and, like subserosal leiomyomas, may public health impact of leiomyomas, little is be either pedunculated or sessile. Tumors in sub- known about their cause. The most important serosal and intramural locations comprise the aspect of the etiology of fibroids - the initiator(s)- majority (95%) of all leiomyomas; submucous remains unknown. Several theories have been leiomyomas make up the remaining 5% (1). advanced. One hypothesis states that increased The clinical sequelae of leiomyomas, which may levels of estrogen and progesterone result in an depend on their location within the uterus, may be increased mitotic rate that may contribute to associated with a spectrum of symptoms, includ- myoma formation by increasing the likelihood of ing excessive menorrhagia, severe abdominal somatic mutations (15). Another favors an inher- 182 J Reprod Infertil, Vol 12, No 3, Jul/ Sept 2011 Medikare V, et al. JRI ent abnormality in the myometrium of individuals therapy further supports the importance of estro- who develop fibroids, based upon the finding of gen. The estrogen hypothesis has also been sup- significantly increased levels of estrogen receptors ported by clinical trials evaluating the medical (ER) in the myometrium of fibroid uteri (13). treatment of myomas with GnRH agonists, the More recently, growth factors have been shown effective result of which is hypoestrogenism to mediate the growth-promoting effects of estro- accompanied by regression of the fibroids (19). gen and play an important role in the development Progesterone: Progesterone is also thought to of fibroid tumors (1). Growth factors, proteins/ play a role in fibroid growth which is supported polypeptides produced locally by smooth muscle by clinical studies. For example, fibroid size cells and fibroblasts control the proliferation of increases during treatment with synthetic proges- cells and appear to stimulate myoma growth, terones. In contrast to GnRH agonist therapy primarily by increasing the extracellular matrix. alone which has been shown to reduce uterine Some of the identified myoma-related
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