Somatic mutations in endometrial epithelium: biological insights and emerging in vitro models

The human endometrium is a complex, dynamic and poorly understood tissue involving monthly cyclical regeneration likely from adult stem/progenitor cells. This regeneration is associated with reproductive pathologies, such as endometriosis and adenomyosis. Endometrial epithelial cells have rates of mutations that are higher than expected for non-malignant tissue. Many of these mutations occur in known cancer-driver genes and can be inherited by endometriosis or adenomyosis lesions. The impact of these mutations on endometrial function and their contribution to endometrial pathologies is unclear. This gap in knowledge is partly due to the lack of suitable in vitro models for studying their effects on endometrial epithelial function. In this manuscript, we present a narrative review of the mutation landscape of the endometrium, their potential means of acquisition, and methods to study their consequences. Cataloguing and studying the role of somatic mutations will help us to understand their contribution to endometrial disease. Identifying their molecular and functional consequences will improve diagnostics, facilitate targeted treatment, and provide a step towards the personalisation of treatment for endometrial pathologies.