Whole-genome DNA sequencing studies of normal endometrial glandular tissue have revealed the frequent presence of somatic “driver” mutations in cancer-related genes. These findings were published in Nature.
While the acquisition of mutations over time is believed to be a characteristic of all somatic cells, data are limited on how it occurs in normal tissues. Nevertheless, the study authors noted that “[t]he characterization of the mutational landscapes of normal tissues is advancing our understanding of the succession of intermediate neoplastic stages between normal cells and the cancers that originate from them.”
One of the rationales for focusing on the endometrium of the uterus was related to its highly dynamic physiology during the reproductive years in response to fluctuating hormone levels, as well as its composition of stromal cells covered by a surface epithelium that is contiguous with embedded glandular epithelium. Although the contiguity of the surface epithelial sheet and the glandular tissue is disrupted during menstruation, it is subsequently restored by stem cells within retained embedded glands.
In this study, 292 normal endometrial glands were isolated using laser-capture microdissection from 28 women between the ages of 19 and 81 years. Comparisons of whole-exome DNA sequencing results for these tissues with matched specimens of other types of normal tissue from the same individual were used to identify somatic mutations in the endometrial glandular tissue. Corresponding data on patient age and parity allowed for the exploration of these factors on the rate and timing of somatic driver mutations in normal glandular tissue of the endometrium.
Some of the key findings of this study included the following:
- Analyses of the fractions of variant alleles showed that each gland was comprised of cells that were mostly descended from the same progenitor cell; hence, they represented expansions of cell clones.
- The cellular clonality of the endometrial glands was independent of the presence or absence of somatic driver mutations, although driver mutations in cancer-related genes were detected in many of the specimens.
- Wide variations were observed regarding the percentage of glands with 1 or more driver mutations, as well as the mean number of somatic driver mutations, and the number of different somatic driver mutations for each individual, although these values were much lower than those observed other studies evaluating endometrial cancer specimens.
- The mutational burden of somatic driver mutations was found to be predominantly influenced by individual age, with 29 base substitutions estimated to occur during each year of adulthood; furthermore, the likelihood of driver-containing clone colonization was positively associated with age but negatively associated with parity.
- Driver mutations were found in many different genes, including ERBB2, ERBB3, FGFR2, HRAS, KRAS, BRAF, PIK3CA, PIK3R1, ARHGAP35, RRAS2, NF1, PPP2R1A, PTEN, ZFHX3, FOXA2, KMT2D, ARID5B, and FBXW7.
- An approximation of the timing of the appearance of these driver mutations in individuals was estimated using phylogenetic trees that were constructed by comparing sequencing results for different endometrial glands of varying proximity. Results of these analyses, which relied of the use of a constant somatic mutation rate, suggest that cell clones with somatic driver mutations can colonize the endometrium as early as the first decade of life.
In their concluding remarks, the study authors noted that their “results show that mutational landscapes differ markedly between normal tissues — perhaps shaped by differences in their structure and physiology — and indicate that the procession of neoplastic change that leads to endometrial cancer is initiated early in life.”
Reference
Moore L, Leongamornlert D, Coorens THH, et al. The mutational landscape of normal human endometrial epithelium [published online April 22, 2020]. Nature. doi: 10.1038/s41586-020-2214-z
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Somatic Driver Mutations Leading to Endometrial Cancer Occur Early in Life - Cancer Therapy Advisor
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