Sigugeir Ólafsson, Ragnheiður Árnadóttir and Kári Stefánsson
Introduction
Endometriosis is a disease characterized by the presence of endometrial cells outside the uterus. The developmental origins of the endometriotic lesions, and their mechanisms of spread within the pelvis continue to be debated. All cells of the body accrue somatic mutations with time, with mutations shared between distant cells implying shared ancestry.
Methods
We used laser capture microscopy to isolate individual endometrial glands from lesional tissue biopsies and matched normal endometrium. The microdissections comprise 200-1000 cells, all derived from the same stem cell. We performed whole-genome sequencing of hundreds of glands from 25 patients to identify the somatic mutations present and build phylogenetic trees.
Results
We show that endometriosis lesions are comprised of several groups of unrelated glands and have not been seeded by single cells. This is true of both superficial and deep-infiltrating lesions and of endometriomas. Furthermore, we show that lesions removed from different sites of the body are derived from distinct cells of origin, indicating that each arose through an independent seeding event as opposed to “metastasis-like” spread from a founder lesion. Locally however, there is evidence of continued, post-seeding, growth, and Darwinian competition between mutant cell clones many of which harbour mutations in known drivers of uterine carcinomas such as KRAS and PIK3CA.
Conclusions
We provide unparalleled insights into the developmental origins of endometriotic lesions, placing significant constraints on existing theories of the aetiology of this poorly understood disease.
