Spatiotemporal dynamics of clonal selection and diversification in normal endometrial epithelium

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.

Somatic variation in normal tissues: friend or foe of cancer early detection?

“…Unlike normal colon and liver, mutant clones almost completely replace non-inflamed endometrium by menopause [29][30][31] . This is likely facilitated by the 'rhizome' structure of the endometrial epithelium, in which vertical glands acquire additional mutations during every menstrual cycle 32 .…”

Challenges of proving a causal role of somatic mutations in the aging process

“…A new concept that is starting to emerge is that somatic variation and the life‐long modification of each cell's genome could play a positive role in the adaptation to environmental challenges and be a critical factor shaping successful responses to tissue damage and tissue evolution. Few examples have been reported, including tissue repair during liver disease (Zhu et al, 2019 ), endometrial regeneration during menstrual cycle (Yamaguchi et al, 2022 ), and clearance of malignant clones in the esophagus (Colom et al, 2021 ).…”

Obesity alters the mouse endometrial transcriptome in a cell context-dependent manner

“…Recently, several studies have identified that somatic driver mutations that are thought to contribute to EC pathogenesis, including PIK3CA , KRAS and PIK3R1 , can exist in normal uteri without cancer [ 69 – 72 ]. We have shown that obesity regulates inflammatory pathway genes in the endometrial epithelia and disrupt the peripheral clock in the endometrial stroma.…”