Uterine leiomyomas represent the most common benign gynecologic tumor. These hormone-dependent smooth-muscle formations occur with an estimated prevalence of ~70% among women of reproductive age and cause symptoms including pain, abnormal uterine bleeding, infertility, and recurrent abortion. Despite the prevalence and public health impact of uterine leiomyomas, available treatments remain limited. Among the potential causes of leiomyomas, early hormonal exposure during periods of development may result in developmental reprogramming via epigenetic changes that persist in adulthood, leading to disease onset or progression. Recent developments in unbiased high-throughput sequencing technology enable powerful approaches to detect driver mutations, yielding new insights into the genomic instability of leiomyomas. Current data also suggest that each leiomyoma originates from the clonal expansion of a single transformed somatic stem cell of the myometrium. In this review, we propose an integrated cellular and molecular view of the origins of leiomyomas, as well as paradigm-shifting studies that will lead to better understanding and the future development of non-surgical treatments for these highly frequent tumors.
The absence of standardized molecular profiling to differentiate uterine leiomyosarcomas versus leiomyomas represents a current diagnostic challenge. In this study, we aimed to search for a differential molecular signature for these myometrial tumors based on artificial intelligence. For this purpose, differential exome and transcriptome-wide research was performed on histologically confirmed leiomyomas (n = 52) and leiomyosarcomas (n = 44) to elucidate differences between and within these two entities. We identified a significantly higher tumor mutation burden in leiomyosarcomas vs. leiomyomas in terms of somatic single-nucleotide variants (171,863 vs. 81,152), indels (9491 vs. 4098), and copy number variants (8390 vs. 5376). Further, we discovered alterations in specific copy number variant regions that affect the expression of some tumor suppressor genes. A transcriptomic analysis revealed 489 differentially expressed genes between these two conditions, as well as structural rearrangements targeting ATRX and RAD51B. These results allowed us to develop a machine learning approach based on 19 differentially expressed genes that differentiate both tumor types with high sensitivity and specificity. Our findings provide a novel molecular signature for the diagnosis of leiomyoma and leiomyosarcoma, which could be helpful to complement the current morphological and immunohistochemical diagnosis and may lay the foundation for the future evaluation of malignancy risk.
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