Transcriptome differences in lesions by color, and cancer mutations in endometriosis

ABSTRACT: Endometriosis is a disease where cells similar to those of the uterine lining grow outside of the uterus, embedding into tissues and organs in the abdominal cavity, forming lesions and causing pain and infertility. Previous studies in patients with endometriosis identified single nucleotide polymorphisms associated with the disease, as well as somatic mutations in cancer-related genes. Here, we use bulk RNA sequencing to determine transcriptome mutation profiling and differentially expressed genes in endometriotic lesions, peritoneum and eutopic endometrium of patients with endometriosis and control patients. Differential gene expression analysis revealed differences in the transcriptome in lesions based on their color, specifically increased inflammatory processes in red lesions compared to clear lesions. Furthermore, lesions expressed an increase in cell proliferation and estrogen response genes compared to eutopic endometrium. We identified an increased occurrence of somatic mutations in cancer-associated genes ARID1A, KRAS, PIK3CA, ARHGAP35 and PBRM1, which were conserved between lesions, peritoneum and eutopic endometrium, in patients with endometriosis without cancer. These mutations arising from eutopic endometrium may have a role in the establishment and progression of the disease. Importantly, our findings suggest that excision of the visible endometriotic lesion tissue during surgery may not be sufficient for complete removal of the lesion, leading to recurrence. LAY SUMMARY: Endometriosis is a condition in which tissue similar to the lining of the uterus (endometrium) grows on pelvic organs, causing pain and affecting fertility. We used RNA sequencing to measure differences in gene expression across three types of tissues: lesions, endometrium, and peritoneum (the membrane that covers internal organs where endometriosis lesions grow). We found that red lesions expressed more inflammation-related genes than clear lesions, and that endometriosis lesions had more signs of cell growth and estrogen response than the other tissues. We also found mutations in genes linked to cancer across the three tissues in patients without cancer. These findings suggest that endometriosis may start or spread from changes in the uterine lining, and that removing only the visible lesions during surgery may not always remove all of the disease.