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.
Highlights
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
We conducted target-gene sequencing of 112 genes in 891 normal endometrial glands from the uteri of 32 subjects ranging in age from 21 to 53 years old (Fig. 1a, Supplementary Table 1 and Supplementary Data)
We explored mutational signatures characterizing the mutational processes operative in normal endometrial glands, where the spectrum of somatic single-nucleotide variants (SNVs) with high mutant allele frequencies (MAFs) was fitted to a set of the Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures[34] (“Methods”)
Summary
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. Cells carrying cancer-associated gene mutations are thought to manifest increased cellular fitness over their neighboring cells and to be positively selected within normal tissues[25] It remains to be elucidated when and how mutant clones expand their territories in normal tissue. Combined with the estimation of chronological ages at which genome events such as clonal expansions and somatic copy number alterations occurred, our sequencing analyses preserving the spatial information of endometrial glands provide fundamental clues to understand the spatiotemporal dynamics of clones with cancerassociated gene mutations in the normal endometrium
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