We review recent studies dealing with the molecular genetics and basic results of omics analysis of uterine leiomyoma (LM)—a common benign muscle tumor of the uterus. Whole genome studies of LM resulted in the discovery of many new gene nets and biological pathways, including its origin, transcriptomic, and epigenetic profiles, as well as the impact of the inter-cell matrix in LM growth and involvement of microRNA in its regulation. New data on somatic cell mutations ultimately involved in the origin, distribution and growth of LM are reviewed. Putative identification of LM progenitor SC (stem cells) giving rise to maternal fibroid nodes and junctional zones provide a new clue for hypotheses on the pathogenomics of LM. The reviewed data are consistent with at least two different but probably intimately interacted molecular mechanisms of LM. One of them (the genetic hypothesis) is focused primarily on the MED12 gene mutations and suggests its onset in the side population of embryonic myoblasts of the female reproductive system, which later gave rise to multiple small and medium fibroids. The single and usually large-size fibroids are induced by predominantly epigenetic disorders in LM SC, provoked by enhanced expression of the HMGA2 gene caused by its hypomethylation and epigenetic deregulation enhanced by hypoxia, muscle tension, or chromosome instability/aberrations. The pathogenomics of both genetic and epigenetic programs of LM with many peculiarities at the beginning later became rather similar and partly overlapped due to the proximity of their gene nets and epigenetic landscape. Pathogenomic studies of LM open ways for elaboration of novel strategies of prevention and treatment of this common disease.

Uterine leiomyomas (ULs) are common benign tumors affecting women of different ethnicities. A large proportion of UL has mutations in MED12. Multiple and solitary ULs usually manifest with different severities, suggesting that their origin and growth pattern may be driven by different molecular mechanisms. Here, we compared the frequency and the spectrum of MED12 exon 2 mutations between multiple (n=82) and solitary (n=40) ULs from Russian patients. Overall, we detected MED12 exon 2 mutations in 51.6% (63/122) of ULs. The frequency of MED12 exon 2 mutations was almost two-fold higher in samples from the multiple UL patients than in those from the solitary UL patients - 61% (50/82) versus 32.5% (13/40). The increased MED12 exon 2 mutation frequency in the multiple ULs was not accompanied by significant alterations in the spectrum of mutation categories, which included missense mutations, deletions, splicing defects, and multiple (double/triple) mutations. Each mutation category had a unique mutation set, comprising both frequent and rarely encountered mutations, which did and did not overlap between the studied groups, respectively. We conclude that in contrast to the solitary ULs, the multiple ULs predominantly originate through MED12-associated mechanisms. The nature of these mechanisms seems to be similar in solitary and multiple ULs, as they contain similar mutations. In multiple UL patients, they are likely to be nonsporadic, indicating the existence of specific factors predisposing to multiple UL development. These data suggest that to clearly understand UL pathogenesis, solitary and multiple tumors should probably be analyzed as separate sets.

For over 100 years, endometriosis, as a chronic, estrogendependent, inflammatory, heritable disease affecting approximately 5-10% of women in reproductive age has been the focus of clinicians and scientists. In spite of numerous environmental, genetic, epigenetic, endocrine, and immunological studies, our knowledge of endometriosis is still fragmentary, and its precise pathophysiology and pathogenomics remain a mystery. The implementation of new technologies has provided tremendous progress in understanding the many intrinsic molecular mechanisms in the development of endometriosis, with progenitor and stem cells (SCs) of the eutopic endometrium as the starting players and endometriotic lesions as the final pathomorphological trait. Novel data on the molecular, genetic, and epigenetic mechanisms of the disease are briefly outlined. We hypothesize the existence of an endometriosis development genetic program (EMDP) that governs the origin of endometrium stem cells programmed for endometriosis (1), their transition (metaplasia) into mesenchymal SCs (2), and their invasion of the peritoneum and progression to endometriotic lesions (3). The pros and cons of the recent unifying theory of endometriosis are also discussed. Complex genomic and epigenetic interactions at different stages of the endometriosis process result in different forms of the disease, with specific features and clinical manifestations. The significance of the EMDP in elaborating a new strategy for endometriosis prediction, prevention, and treatment is discussed.