Chromosomal instability associated with pathogenesis in adenomyosis.

e22517 Background: Uterine adenomyosis is a benign condition in which endometrium-like epithelial and stromal tissue appear in the myometrium, but easily concurrent with uterine cancer and other diseases. To date, few investigations have explored the molecular mechanism of adenomyosis. This research is the first report that found the association between chromosomal instability and pathogenesis in adenomyosis. Methods: Whole exome (̃39Mb CDS of over 18,000 genes; WES) and RNA sequencing were conducted on a total of 57 adenomyosis patients enrolled in this study from 2018 to 2020, including 57 normal endometrium (EN), 57 adenomyosis (AM) and 11 endometrioses (EMT) samples. Genomic test results including somatic SNVs and CNVs as well as the whole genome duplication status were determined, which were all analyzed correlated with clinical factors. Results: We identified the presence of whole genome doubling event in 19 specimens from 16 adenomyosis patients (grouped as WGD, the other 41 patients grouped as noWGD), related to 7 normal endometrium (EN), 9 adenomyosis (AM) and 3 endometriosis (EMT) samples, which was significant with p value of 4.5e-12 by means of Wilcoxon rank sum test. Disease Free Survival (DFS) of WGD patients was significantly shorter than noWGD patients (Wilcoxon rank sum test: P = 2.42e-04), which indicated that WGD group has early on-set in adenomyosis. Estrogen therapy was applied to 31 patients before uterectomy (11 in WGD group and 20 in noWGD group), and the effectiveness of the treatment was significantly higher in WGD patients (Fisher’s exact test: P = 0.02). We found that one third adenomyosis performed whole genome doubling events, which leaded to the early on-set of this disease and significantly sensitive to estrogen therapy. Cellular stressors are extensive correlated with the generation of polyploid cells in a diploid organism form by cell proliferation progress. Compared with the normal and energy-intensive cell differentiation process, cell proliferation offers a “fast but cheap” solution under stress. Our results suggested that when cell differentiation in uterine could not be carried out properly, cell proliferation would have performed instead and produced more polyploid cells, shown as whole genome doubling events. While this circumstance would have been relieved when easing the metabolic stress with estrogen treatment. Conclusions: Our results explored the strong association between chromosomal instability and pathogenesis of adenomyosis and assumed that polyploidy caused by abnormal cell proliferation might be the molecular mechanism of uterine adenomyosis. More accurate verdict could be concluded through larger scale cohort study.