Spatiotemporal dynamics of clonal selection and diversification in normal endometrial epithelium

Manako Yamaguchi, Hirofumi Nakaoka (), Kazuaki Suda, Kosuke Yoshihara (), Tatsuya Ishiguro, Nozomi Yachida, Kyota Saito, Haruka Ueda, Kentaro Sugino, Yutaro Mori, Kaoru Yamawaki, Ryo Tamura, Sundaramoorthy Revathidevi, Teiichi Motoyama, Kazuki Tainaka, Roel G. W. Verhaak, Ituro Inoue () and Takayuki Enomoto ()
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Manako Yamaguchi: Niigata University Graduate School of Medical and Dental Sciences
Hirofumi Nakaoka: National Institute of Genetics
Kazuaki Suda: Niigata University Graduate School of Medical and Dental Sciences
Kosuke Yoshihara: Niigata University Graduate School of Medical and Dental Sciences
Tatsuya Ishiguro: Niigata University Graduate School of Medical and Dental Sciences
Nozomi Yachida: Niigata University Graduate School of Medical and Dental Sciences
Kyota Saito: Niigata University Graduate School of Medical and Dental Sciences
Haruka Ueda: Niigata University Graduate School of Medical and Dental Sciences
Kentaro Sugino: Niigata University Graduate School of Medical and Dental Sciences
Yutaro Mori: Niigata University Graduate School of Medical and Dental Sciences
Kaoru Yamawaki: Niigata University Graduate School of Medical and Dental Sciences
Ryo Tamura: Niigata University Graduate School of Medical and Dental Sciences
Sundaramoorthy Revathidevi: National Institute of Genetics
Teiichi Motoyama: Niigata University Graduate School of Medical and Dental Sciences
Kazuki Tainaka: Niigata University
Roel G. W. Verhaak: The Jackson Laboratory for Genomic Medicine
Ituro Inoue: National Institute of Genetics
Takayuki Enomoto: Niigata University Graduate School of Medical and Dental Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28568-2

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