Document Type

Article

Publication Date

2-17-2022

Publication Title

Nat Commun

Keywords

JGM, Adult, Biomarkers, Tumor, Carcinogenesis, Clonal Evolution, DNA Mutational Analysis, Endometrial Neoplasms, Endometrium, Epithelium, Female, Humans, Menstrual Cycle, Middle Aged, Mutation, Mutation Rate, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Spatio-Temporal Analysis, Young Adult

JAX Source

Nat Commun 2022 Feb 17; 13(1):943

Volume

13

Issue

1

First Page

943

Last Page

943

ISSN

2041-1723

PMID

35177608

DOI

https://doi.org/10.1038/s41467-022-28568-2

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.

Comments

This article is licensed under a Creative Commons Attribution 4.0 International License,

Download

Share

COinS