Common and specific gene signatures among three different endometriosis subtypes.

Li Jiang,Yuanyuan Han,Xiaoling Fang,Mengmeng Zhang,Sixue Wang

doi:10.7717/peerj.8730

Abstract

AimsTo identify the common and specific molecular mechanisms of three well-defined subtypes of endometriosis (EMs): ovarian endometriosis (OE), peritoneal endometriosis (PE), and deep infiltrating endometriosis (DIE).MethodsFour microarray datasets: GSE7305 and GSE7307 for OE, E-MTAB-694 for PE, and GSE25628 for DIE were downloaded from public databases and conducted to compare ectopic lesions (EC) with eutopic endometrium (EU) from EMs patients. Differentially expressed genes (DEGs) identified by limma package were divided into two parts: common DEGs among three subtypes and specific DEGs in each subtype, both of which were subsequently performed with the Kyoto Encyclopedia of Genes (KEGG) pathway enrichment analysis. The protein-protein interaction (PPI) network was constructed by common DEGs and five hub genes were screened out from the PPI network. Besides, these five hub genes together with selected interested pathway-related genes were further validated in an independent OE RNA-sequencing dataset GSE105764.ResultsA total of 54 EC samples from three EMs subtypes (OE, PE, DIE) and 58 EU samples were analyzed, from which we obtained 148 common DEGs among three subtypes, and 729 specific DEGs in OE, 777 specific DEGs in PE and 36 specific DEGs in DIE. The most enriched pathway of 148 shared DEGs was arachidonic acid (AA) metabolism, in which most genes were up-regulated in EC, indicating inflammation was the most common pathogenesis of three subtypes. Besides, five hub genes AURKB, RRM2, DTL, CCNB1, CCNB2 identified from the PPI network constructed by 148 shared DEGs were all associated with cell cycle and mitosis, and down-regulated in EC, suggesting a slow and controlled proliferation in ectopic lesions. The KEGG pathway analysis of specific DEGs in each subtype revealed that abnormal ovarian steroidogenesis was a prominent feature in OE; OE and DIE seems to be at more risk of malignant development since both of their specific DEGs were enriched in the pathways in cancer, though enriched genes were different, while PE tended to be more associated with dysregulated peritoneal immune and inflammatory microenvironment.ConclusionBy integrated bioinformatic analysis, we explored common and specific molecular signatures among different subtypes of endometriosis: activated arachidonic acid (AA) metabolism-related inflammatory process and a slow and controlled proliferation in ectopic lesions were common features in OE, PE and DIE; OE and DIE seemed to be at more risk of malignant development while PE tended to be more associated with dysregulated peritoneal immune and inflammatory microenvironment, all of which could deepen our perception of endometriosis.

Highlights

Endometriosis (EMs), characterized by the growth of endometrium-type tissue outside the uterine cavity, is a common and usually chronic inflammatory disorder, affecting 5–10% of women in their reproductive years (Zondervan et al, 2018)
Since the classic retrograde menstruation hypothesis (Sampson, 1927) that during menstrual uterine contractions, endometrial fragments via trans-tubal reflux flowed to implant onto the peritoneum and abdominal organs could not explain the fact that 76–90% of women experienced retrograde menstruation but not all of these women suffered from EMs (Blumenkrantz et al, 1981), there must exist other mechanisms facilitating the development of EMs
The 5 hub nodes RRM2, AURKB, DTL, CCNB1, CCNB2 identified from the protein-protein interaction (PPI) network constructed by148 shared Differentially expressed genes (DEGs) were all associated with cell cycle and mitosis, and down-regulated in the ectopic lesions in our analysis while always up-regulated in cancer tissues (Wang et al, 1997; Kolesar et al, 2009; Takashima et al, 2014; Kobayashi et al, 2015; Chieffi, 2018), promoting excessive proliferation, which suggested limited and controlled proliferative activity in EMs endometriotic lesions, distinct from cancerous proliferation feature

Summary

Introduction

Endometriosis (EMs), characterized by the growth of endometrium-type tissue outside the uterine cavity, is a common and usually chronic (long-term) inflammatory disorder, affecting 5–10% of women in their reproductive years (Zondervan et al, 2018). Since the classic retrograde menstruation hypothesis (Sampson, 1927) that during menstrual uterine contractions, endometrial fragments via trans-tubal reflux flowed to implant onto the peritoneum and abdominal organs could not explain the fact that 76–90% of women experienced retrograde menstruation but not all of these women suffered from EMs (Blumenkrantz et al, 1981), there must exist other mechanisms facilitating the development of EMs. On the other hand, as early as 1997, Nisolle and Donnez provided morphological and histochemical evidence indicating that three main subtypes of endometriosis: ovarian endometriosis (OE), peritoneal endometriosis (PE), and deep infiltrating endometriosis (DIE), should be considered different entities, though they shared the histologic features of endometrial glands and stroma (Nisolle & Donnez, 1997). Investigating the common and specific mechanisms among different EMs subtypes may provide new insight into the pathogenesis of endometriosis. Due to the limited information as well as samples available from single cohorts, few integrative analyses of EMs subtypes were conducted

Results

Discussion

Conclusion