Pathogenetic Gene Changes of Eutopic Endometrium in Patients with Ovarian Endometriosis
Endometriosis is a complex and multifactorial condition characterized by the presence of endometrial tissue outside the uterine cavity, leading to symptoms such as chronic pain, infertility, and the formation of nodules or masses. Despite extensive research, the exact pathogenesis of endometriosis remains elusive. Traditional theories, including retrograde menstruation, immune dysfunction, inflammation, and hormonal imbalances, have provided partial explanations but fail to fully account for the disease’s development. Recent studies have highlighted the potential role of eutopic endometrium—the endometrial tissue within the uterine cavity—in the pathogenesis of endometriosis. This tissue may possess intrinsic abnormalities that enable endometrial fragments to adhere, invade, and proliferate outside the uterus. This study employs whole exome sequencing (WES) and gene chip technology to investigate the genetic alterations in eutopic endometrium of patients with ovarian endometriosis (OEM) and their potential contribution to the disease.
Study Design and Methodology
The study included patients with OEM who underwent surgical treatment at Peking Union Medical College Hospital. The control group consisted of patients who underwent hysterectomy due to cervical lesions, with no history of endometriosis or other benign or malignant uterine or ovarian diseases. Patients with a family history of Lynch syndrome, systemic malignancies, or immune system diseases were excluded. Three patients with sporadic OEM and three control patients were selected for WES. Samples collected included peripheral venous blood, eutopic endometrium, and OEM lesions from the case group, as well as endometrial tissue from the control group.
High-throughput sequencing was performed using the Illumina HiSeq2500 platform, generating 101-base pair paired-end reads with an average of 15 gigabytes of data per sample. The process involved whole exome sequence capture, bioinformatics analysis, and functional prediction of identified mutations. Genes with somatic mutations shared between eutopic endometrium and OEM lesions were selected for further validation using gene chip technology. A cohort of 18 patients with OEM was selected from the pathological database for this purpose.
Results of Whole Exome Sequencing
Analysis of single nucleotide variant (SNV) mutations in the six patients revealed no overlap in mutation sites between eutopic endometrium, OEM lesions, and control endometrial tissues. In the three OEM patients, an average of 25 somatic mutations were identified per patient, most of which were located in intergenic regions. Five, five, and three common mutations were found in patients one, two, and three, respectively. These 13 mutation sites were located in ten genes: DTX2, BAGE4, BAGE3, BAGE2, BAGE5, LPA, AQP7, PCSK5, SEC14L1, CST2, FRG1, HECTD4, and ZFYVE21. No common mutation sites or genes were shared among the three patients.
Gene Chip Validation
A custom gene chip was designed to include the ten SNV-mutated genes identified in the WES analysis. Validation in 18 OEM patients revealed 105 non-silent mutations across 36 samples (eutopic endometrium and OEM lesions). Of these, 86 mutations (82%) were common to both eutopic endometrium and ectopic lesions. Eleven patients (61%) exhibited two or more common mutations, all of which were missense mutations. These mutations were predominantly located in the LPA and PCSK5 genes, with eight patients showing at least one LPA mutation and nine patients showing at least one PCSK5 mutation.
Role of LPA and PCSK5 in Endometriosis
The LPA gene encodes apolipoprotein(a) (Apo[a]), a component of lipoprotein(a) (LP[a]). LP[a] has been implicated in inflammatory processes, interacting with cytokines such as tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1). While no direct link between LP[a] and endometriosis has been established, LP[a] may contribute to oxidative stress, potentially promoting the transformation of eutopic endometrium into ectopic lesions. Further research is needed to explore the expression of LPA in endometrial, peritoneal, and ovarian tissues and its role in endometriosis pathogenesis.
PCSK5, a proprotein convertase, processes and activates precursors of cytokines and adhesion factors such as matrix metalloproteinases, N-cadherin, and insulin-like growth factors. These factors are known to play critical roles in the development of endometriosis. The study identified multiple mutation sites in PCSK5, suggesting its potential involvement in the disease. However, further investigation is required to elucidate the expression and functional impact of PCSK5 in endometriosis.
Clinical Implications and Future Directions
The findings of this study highlight the potential significance of LPA and PCSK5 mutations in the pathogenesis of ovarian endometriosis. These mutations were common to both eutopic endometrium and ectopic lesions in a majority of the patients studied, suggesting they may serve as molecular markers for the disease. However, their diagnostic utility and the clinical manifestations associated with these mutations require further investigation.
This study provides new insights into the molecular mechanisms underlying endometriosis and offers potential targets for diagnostic and therapeutic strategies. By identifying specific genetic alterations in eutopic endometrium, the research opens avenues for exploring the role of these mutations in disease development and progression. Future studies should focus on validating these findings in larger cohorts and investigating the functional consequences of LPA and PCSK5 mutations in endometriosis.
Conclusion
This study employed whole exome sequencing and gene chip technology to explore the genetic alterations in eutopic endometrium of patients with ovarian endometriosis. The identification of somatic mutations in genes such as LPA and PCSK5 provides new insights into the molecular mechanisms of endometriosis. These findings suggest that genetic abnormalities in eutopic endometrium may play a critical role in the development of ectopic lesions, offering potential targets for future diagnostic and therapeutic approaches. Further research is needed to validate these findings and explore their clinical implications.
doi.org/10.1097/CM9.0000000000000195
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