Genetic alteration of mRNA editing enzyme APOBEC3B in the pathogenesis of ovarian endometriosis

Vaishnavi Balasubramanian; Roshni Saravanan; Srikanth Swamy Swaroop Balamurugan; Swetha Rajendran; Leena Dennis Joseph; Bhawna Dev; Bhuvana Srinivasan; Nandhini Balunathan; Gouthaman Shanmugasundaram; Gopal Gopisetty; Kumaresan Ganesan; Suresh Kumar Rayala; Ganesh Venkatraman

doi:10.1016/j.rbmo.2024.104111

Genetic alteration of mRNA editing enzyme APOBEC3B in the pathogenesis of ovarian endometriosis

Reprod Biomed Online. 2024 May 23;49(5):104111. doi: 10.1016/j.rbmo.2024.104111. Online ahead of print.

Affiliations

¹ Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai-600116, India.
² Department of Pathology, Sri Ramachandra Medical College, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, 600116, India.
³ Department of Radiology, Sri Ramachandra Medical College Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, 600116, India.
⁴ Department of Obstetrics and Gynecology, Sri Ramachandra Medical College Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, 600095, India.
⁵ Department of Surgical Oncology, Apollo Specialty Hospitals Vanagaram, Chennai, 600116, India.
⁶ Department of Molecular Oncology, Cancer Institute (W.I.A), Adayar, Chennai, 600036, India.
⁷ Unit of Excellence in Cancer Genetics, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, 625021, India.
⁸ Department of Biotechnology, Indian Institute of Technology Madras, Chennai, 600036, India.. Electronic address: rayala@iitm.ac.in.
⁹ Department of Bio-Medical Sciences, School of Bio Sciences & Technology, Vellore Institute of Technology Vellore, Vellore, 632014, India.. Electronic address: ganesh.v@vit.ac.in.

PMID: 39197402
DOI: 10.1016/j.rbmo.2024.104111

Abstract

Research question: What are the specific genetic alterations and associated network in endometriotic cells responsible for the disease pathogenesis?

Design: Case control experimental study involving 45 women with endometriosis who underwent laparoscopic surgery (case) and 45 normal samples from women undergoing total abdominal hysterectomy (control). The endometrial samples were subjected to whole exome sequencing (WES) of endometriotic tissue and copy number variation analysis. Validation of gene hits were obtained from WES using polymerase chain reaction techniques, immunological techniques, in-silico tools and transgenic cell line models.

Results: Germline heterozygous deletion of mRNA editing enzyme subunit APOBEC3B was identified in about 96% of endometriosis samples. The presence of germline deletion was confirmed with blood, endometrium and normal ovary samples obtained from the same patient. APOBEC3B deletions resulted in a hybrid protein that activates A1CF. APOBEC3B deletion can be a major cause of changes in the endometriotic microenvironment, and contributes to the pathogenesis and manifestation of the disease. The effect of APOBEC3B deletion was proved by in-vitro experiments in a cell line model, which displayed endometriosis-like characteristics. APOBEC3B germline deletion plays a major role in the pathogenesis of endometriosis, which is evident by the activation of A1CF, an increase in epithelial to mesenchymal transition, cellular proliferation, inflammation markers and a decrease in apoptosis markers.

Conclusion: The deleterious effects caused by APOBEC3B deletion in endometriosis were identified and confirmed. These results might provide a base for identifying the complete pathogenetic mechanism of endometriosis, thereby moving a step closer to better diagnosis and treatment options.

Keywords: A1CF; APOBEC3B deletion; Endometriomas; Endometriosis; Pathogenesis; Whole exome sequencing.