Alterations of DNA methylation were associated with the rapid growth of cortisol-producing adrenocortical adenoma during pregnancy

Chuan Wang,Ruxing Zhao,Yujing Sun,Jinbo Liu,Gangli Gu,Kai Liang,Peng Su,Ruoqi Feng,Xiaofei Yin,Xiaofang Zhang,Mingyue Xu,Ruiying Feng,Xuewen Jiang

doi:10.1186/s13148-021-01205-3

Chuan Wang, Ruxing Zhao + Show 11 more

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https://doi.org/10.1186/s13148-021-01205-3

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Abstract

BackgroundCortisol-producing adrenocortical adenoma (CPA) during pregnancy rarely occurs in clinic. Growing evidence suggests that DNA methylation plays a key role in adrenocortical adenomas. The present study aims to examine the genome-wide DNA methylation profiles and identify the differences in DNA methylation signatures of non-pregnant and pregnant patients with CPA.ResultsFour pregnant and twelve non-pregnant patients with CPA were enrolled. The pregnant patients with CPA had higher serum cortisol, Estradiol, Progesterone, and human chorionic gonadotropin concentration, while having lower serum FSH (follicle-stimulating hormone) and luteinizing hormone concentrations (P < 0.01). Compared with the non-pregnant patients, the duration is shorter, and the growth rate of the tumor is faster in pregnant patients with CPA (P < 0.05). Morphology and cell proliferation assay showed that the percentage of Ki-67 positive cells in CPA were higher in pregnant group than non-pregnant group (8.0% vs 5.5%, P < 0.05). The DNA methylation analysis showed that Genome-wide DNA methylation signature difference between pregnant and non-pregnant with CPA, that the pregnant group had more hypermethylated DMPs (67.94% vs 22.16%) and less hypomethylated DMPs (32.93% vs 77.84%). The proportion of hypermethylated DMPs was relatively high on chromosomes 1 (9.68% vs 8.67%) and X (4.99% vs 3.35%) but lower on chromosome 2(7.98% vs 12.92%). In pregnant patients with CPA, 576 hypomethylated DMPs and 1109 hypermethylated DMPs were identified in the DNA promoter region. Bioinformatics analysis indicated that the Wnt/β-Catenin pathway, Ras/MAPK Pathway and PI3K-AKT Pathway were associated with the development of CPA during pregnancy.ConclusionsGenome-wide DNA methylation profiling of CPA in non-pregnant and pregnant patients was identified in the present study. Alterations of DNA methylation were associated with the pathogenesis and exacerbation of CPA during pregnancy.

Highlights

Cortisol-producing adrenocortical adenoma (CPA) during pregnancy rarely occurs in clinic
Most studies indicated that an aberrant expression of luteinizing hormone (LH)/human chorionic gonadotropin receptor (LHCGR) in CPA played a critical role in the pathogenesis and exacerbation of CPA during pregnancy [5, 6]
We aimed to identify the differences in DNA methylation signatures of non-pregnant and pregnant patients with CPA, which might be associated with the pathogenesis and exacerbation of CPA during pregnancy

Summary

Introduction

Cortisol-producing adrenocortical adenoma (CPA) during pregnancy rarely occurs in clinic. Growing evidence suggests that DNA methylation plays a key role in adrenocortical adenomas. In non-pregnant patients with CS, adrenocorticotropic hormone (ACTH)-secreting pituitary tumors account for 60–70% of cases [2]. The majority of CS during pregnancy, is caused by cortisol-producing adrenocortical adenoma (CPA) [3]. It was previously suggested that the hormonal metabolic milieu during pregnancy may trigger the development of CPA. Most studies indicated that an aberrant expression of luteinizing hormone (LH)/human chorionic gonadotropin (hCG) receptor (LHCGR) in CPA played a critical role in the pathogenesis and exacerbation of CPA during pregnancy [5, 6]. Cortisol hypersecretion was not observed in all pregnant women [7]. Alternative pathogenic mechanisms of CPA during pregnancy were indicated

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