Uterine leiomyomas (ULs), frequent benign tumours of the female reproductive tract, are associated with a range of symptoms and significant morbidity. Despite extensive research, there is no consensus on essential points of UL initiation and development. The main reason for this is a pronounced inter- and intratumoral heterogeneity resulting from diverse and complicated mechanisms underlying UL pathobiology. In this review, we comprehensively analyse risk and protective factors for UL development, UL cellular composition, hormonal and paracrine signalling, epigenetic regulation and genetic abnormalities. We conclude the need to carefully update the concept of UL genesis in light of the current data. Staying within the framework of the existing hypotheses, we introduce a possible timeline for UL development and the associated key events-from potential prerequisites to the beginning of UL formation and the onset of driver and passenger changes.
Keywords: DNA methylation; HMGA2; MED12; chromosomal rearrangements; chromothripsis; epigenetic abnormalities; histone modifications; intratumoral heterogeneity; non-coding RNAs; uterine leiomyoma.