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

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.

Systems genetics view of endometriosis: a common complex disorder.

Endometriosis is a condition in which cells derived from the endometrium grow outside the uterus, e.g. in the peritoneum (external genital endometriosis). As these cells are under the influence of female hormones, major symptoms of endometriosis are pain, especially during the cycle, and infertility. Numerous hypotheses for the formation of endometriosis can be found in the literature, but there is growing evidence of serious genetic contributions to endometriosis susceptibility. The involvement of genes, steroid hormone metabolism, immunological reactions, receptor formation, inflammation, proliferation, apoptosis, intercellular adhesion, cell invasion and angiogenesis as well as genes regulating the activity of aforementioned enzymes have been suggested. Some more recently suggested candidate genes picked up in genome-wide association studies are involved in oncogenesis, metaplasia of endometrium cells and pathways of embryonic development of the female reproductive system. However, gene mutations proven to be causative for endometriosis have not been identified so far, even though the abnormal expression of candidate genes for endometriosis could be provoked by different epigenetic modifications including DNA methylation, heterochromatization or introduction of regulatory miRNA. We hypothesize that endometriosis is induced by a combination of abnormal genetic and/or epigenetic mutations: the latter pave the way for pathological changes which become irreversible, and according to the "epigenetic landscape" theory, this proceeds to the typical clinical manifestations. Two stages in the endometriosis pathway are suggested: (1) induction of primary endometrial cells toward endometriosis, and (2) implantation and progression of these cells into endometriosis lesions. The model favors endometriosis as an outgrowth of primary cells different in their origin, canalization of pathological processes, manifestation diversity provoked by unique genetic background and epigenetic influences, which result in many different clinical forms of the disease.