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- Title
Spatiotemporal dynamics of clonal selection and diversification in normal endometrial epithelium.
- Authors
Yamaguchi, Manako; Nakaoka, Hirofumi; Suda, Kazuaki; Yoshihara, Kosuke; Ishiguro, Tatsuya; Yachida, Nozomi; Saito, Kyota; Ueda, Haruka; Sugino, Kentaro; Mori, Yutaro; Yamawaki, Kaoru; Tamura, Ryo; Revathidevi, Sundaramoorthy; Motoyama, Teiichi; Tainaka, Kazuki; Verhaak, Roel G. W.; Inoue, Ituro; Enomoto, Takayuki
- Abstract
It has become evident that somatic mutations in cancer-associated genes accumulate in the normal endometrium, but spatiotemporal understanding of the evolution and expansion of mutant clones is limited. To elucidate the timing and mechanism of the clonal expansion of somatic mutations in cancer-associated genes in the normal endometrium, we sequence 1311 endometrial glands from 37 women. By collecting endometrial glands from different parts of the endometrium, we show that multiple glands with the same somatic mutations occupy substantial areas of the endometrium. We demonstrate that "rhizome structures", in which the basal glands run horizontally along the muscular layer and multiple vertical glands rise from the basal gland, originate from the same ancestral clone. Moreover, mutant clones detected in the vertical glands diversify by acquiring additional mutations. These results suggest that clonal expansions through the rhizome structures are involved in the mechanism by which mutant clones extend their territories. Furthermore, we show clonal expansions and copy neutral loss-of-heterozygosity events occur early in life, suggesting such events can be tolerated many years in the normal endometrium. Our results of the evolutionary dynamics of mutant clones in the human endometrium will lead to a better understanding of the mechanisms of endometrial regeneration during the menstrual cycle and the development of therapies for the prevention and treatment of endometrium-related diseases. Through regeneration, the endometrium accumulates somatic mutations that can lead to diseases like endometriosis and cancer. Here, the authors use genomics to analyse normal endometrial glands from different patient cohorts, detect rhizome structures with common clonal ancestors and infer clonal expansion dynamics.
- Subjects
ENDOMETRIUM; EPITHELIUM; MENSTRUAL cycle; GLANDS
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-28568-2