Comparative systems genetics view of endometriosis and uterine leiomyoma: Two sides of the same coin?

Abstract

Endometriosis (EM) and uterine leiomyoma (UL) are two most frequent benign tumors of monoclonal origin affecting about 30% of all women in their reproductive age. Modern molecular technologies have made a tremendous impact in understanding both disorders. Here is the first comparative analysis of molecular mechanisms underlying development of EM and UL as it looks from the platform of systems genetics. Similarities and differences of EM and UL at their incipient stages are enlightened with special emphasis on their gene networks, gene expression, and epigenetic regulation, of pathologic development. The analysis substantiates a new hypothesis postulating tumors as outgrowths of the stem cells with mesenchymal commitment lineage (mSC) which migrate from the endometrium/myometrium junctional zone of the uterus. Comparative analysis has revealed basic similarities of molecular pathogenesis of EM and UL suggesting molecular syntropy of both disorders. Peculiarities of the epigenetic landscape determining development of mSC may explain the existence of different clinical forms of EM and UL as well as their unique clinical manifestation. Some perspectives for practical and scientific application in EM and UL studies of this new hypothesis are outlined.

Catechol-O-methyltransferase Val158Met polymorphism is associated with increased risk of multiple uterine leiomyomas either positive or negative forMED12exon 2 mutations

“…The etiopathogenesis of uterine fibroids remains a focal point in research of benign tumours for several decades 20 21. UL is a polygenic multifactorial disease, thus, suggesting that many factors, including age, parity, ethnicity family history and sex steroid hormonal status may be involved in the initiation of a fibroid tumour growth 4.…”

Pathogenomics of Uterine Fibroids Development

“…Already, the first studies on functional mapping made it possible to confirm the association of LMs with more than 100 genes whose products are included in various metabolic pathways. Important genes for predisposition to LM are the genes for steroid hormones, cytokines, the immune response, and tumor growth factors [5]. At the same time, polymorphism of the PROGINS (progesterone receptor gene) according to individual authors is not a risk factor for the development of LM [40].…”

“…Hundreds of candidate genes and dozens of metabolic pathways make up the LM gene network [5]. The latter includes embryonic developmental genes (WNT and HOX), MED12, steroid hormone metabolism genes and their receptors, collagen genes and ECM metabolism genes, many oncogenes and their suppressors, proliferation and growth factor genes, as well as apoptosis genes and their regulators.…”

“…The widespread introduction of molecular genetic research methods into modern medicine has made it possible to obtain fundamentally new information on the pathomorphological and hormonal causes of the onset and development of LM, as well as on the characteristics of the genome, indicating an important role of heredity in the development of the disease. Genetic factors and molecular mechanisms of pathogenesis of LM have been repeatedly discussed in the scientific literature [3][4][5]. Recent studies searching for the parental (progenitor) cells of LM, as well as systemic (omix) analysis of LM, have significantly deepened and expanded the understanding of the pathogenomics of LM, creating real prerequisites for the development of new promising models of the disease and its targeted therapy.…”

Molecular-genetic determinants of the development of endometriosis

“…На основе современных молекулярных, генетических и эпигенетических данных В.С.Баранов и соавт. указывают на важную роль в развитии эндометриоза мезенхимных стволовых клеток (mSC) и предлагают гипотезу трех критических периодов репрограммирования генома стволовых клеток в развитии этого заболевания: 1-й период -начальные стадии становления и развития женской половой системы (8-10 нед беременности), 2-й период -трансцизия клеток эндометрия в мезенхимные стволовые клетки, 3-й период -становление и развитие эндометриоидных гетеротопий [37][38][39]. В работе выдвигается гипотеза о существовании генетической программы развития эндометриоза, которая управляет происхождением стволовых клеток эндометрия, запрограммированных на развитие эндометриоза, их метаплазией в мезенхимные стволовые клетки с последующей инвазией в брюшину и прогрессией в эндометриоидные Молекулярно-генетические детерминанты развития эндометриоза Molecular-genetic determinants of the development of endometriosis очаги [38].…”