Whole-genome Doubling Associated With Adenomyosis Early Onset And Treatment Effectiveness

BackgroundAdenomyosis is one of the most common benign gynecological disorders,which cause menorrhagia,chronic pelvic pain,dysmenorrhea,and subfertility.It seriously affects the quality of daily life,physical and mental health in women of gestational age.The treatment regimens of adenomyosis varied from hormone therapy,surgery,interventional procedures,and so on.All of thses therapeutic regimens have their own advantages and disadvantages,and no unified and satisfied treatment regimen existed so far.There are many studies related to the pathogenesis of adenomyosis,but it is still worth further exploring the underlying mechanism to provide new ideas for clinical treatment for a lack of satisfied treatment regimens.ObjectivesBy the means of next generation sequencing,the primary objective is to explore the prevalence of WGD events in the fresh sample of endometrium,adenomyosis lesions,and endometriosis lesions.The secondary objectives are to dig the correlation between the WGD events and the adenomyosis onset,and the role of WGD in the effectiveness of hormone therapy.MethodsThe peripheral blood and fresh isolated endometrium,adenomyosis lesions,and endometriosis lesions were obtained from 57 patiens who were diagnosed with adenomyosis and received hysterectomy in Peking Union Medical College Hospital from November 2018 to June 2019.Whole exome sequencing(WES)and RNA sequencing were conducted.Genomic test results were determined including somatic CNVs,SNVs,insertion and deletion,RNA-seq,as well as the WGD events,and the correlation between WGD status and the clinical characteristics was analyzed.The role of WGD events in adenomyosis onset was analyzed by using Kaplan-Meier analysis,while the multivariate analysis was used to determine the indepedent factors related to the effectiveness of hormone therapy.ResultsWe finally enrolled 57 patients with 125 specimens,including 57 endometrium specimens and matched adenomyosis samples and 11 endometriosis specimens.We identified the presence of the WGD events in 19 specimens from 16 patients(28.1%)with adenomyosis(including 7 endometrium,9 adenomyosis samples,and 3 endometriosis samples).There was a significant difference referring to the polyploid between the WGD specimens and non-WGD specimens(Wilcoxon rank sum test,p<0.001).Based on the result of WGD events,patients were divided into WGD group(n=16)and non-WGD group(n=41).Disease free interval(DFI)of patients in WGD group was significantly shorter than those in non-WGD group(p<0.001).What's more,hormone therapy was applied and evaluated in 30 patients before hysterectomy,and 18 patients(including 9 with WGD events)showed treatment effectiveness,12 patients(including 1 with WGD events)showed no treatment effects.There was a significantly higher proportion of patients with WGD events in those having treatment effectiveness(p=0.021).In multivariate analysis,it was revealed that WGD events was the independent factor related to treatment effectiveness(p=0.036).As a estrogen-depedent disease,cell proliferation with less need of energy compete with the energy consuming cell differentiation under the metabolic pressure arising from local high level of estrogen.Thus cell can survive by this "fast but cheap" solution,while the risk of polyploid formation is increased.When hormone therapy was performed,the local metabolic pressure caused by estrogen will be relieved to provide sufficient energy for the energy consuming cell differentiation.This explained why patients with WGD events can get satisfied treatment effect from hormone therapy.No association was found between WGD events and mutational genes in this study.ConclusionsAdenomyosis may also can be deemed as a polyploid disease,and the prevalence of WGD in adenomyosis is 28.1%.The occurrence of WGD events has close correlation with the early onset of adenomyosis and the treatment effectiveness of hormone therapy.However,no clear relationship was found between WGD events and mutational genes.Therefore,WGD events may be an important pathogenesis in adenomyosis.