Endometriosis is characterized by ectopic endometrial-like epithelium and stroma, of which molecular characteristics remain to be fully elucidated. We sequenced 107 ovarian endometriotic and 82 normal uterine endometrial epithelium samples isolated by laser microdissection. In both endometriotic and normal epithelium samples, numerous somatic mutations were identified within genes frequently mutated in endometriosis-associated ovarian cancers. KRAS is frequently mutated in endometriotic epithelium, with a higher mutant allele frequency (MAF) accompanied by arm-level allelic imbalances. Analyses of MAF, combined with multiregional sequencing, illuminated spatiotemporal evolution of the endometriosis and uterine endometrium genomes. We sequenced 109 single endometrial glands and found that each gland carried distinct cancer-associated mutations, demonstrating the heterogeneity of the genomic architecture of endometrial epithelium. Remarkable increases in MAF of mutations in cancer-associated genes in endometriotic epithelium suggest retrograde flow of endometrial cells already harboring cancer-associated mutations, with selective advantages at ectopic sites, leading to the development of endometriosis.

STUDY QUESTION Are there common mutation profiles between epithelial and stromal cells in ovarian endometriotic tissue and the normal endometrium? SUMMARY ANSWER Our study revealed no common mutations between epithelial and stromal cells in ovarian endometriotic tissue and the normal endometrium. WHAT IS KNOWN ALREADY Epithelial cells in both ovarian endometriotic tissue and the normal endometrium harbor somatic mutations in cancer-associated genes such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and KRAS proto-oncogene, GTPase (KRAS). STUDY DESIGN, SIZE, DURATION We performed a retrospective study to identify the mutation profiles of stromal cells in endometriotic tissue and the normal endometrium. We collected 11 endometriotic stroma samples and 10 normal endometrial stroma samples between 2013 and 2017 at a tertiary care center. PARTICIPANTS/MATERIALS, SETTING, METHODS The laser microdissection method was used to obtain stromal cells in ovarian endometriotic and normal endometrial tissues from patients with ovarian endometriosis and/or other non-invasive gynecological diseases. Target gene sequencing was performed to assess and compare the mutation profiles of stromal cells with those of epithelial cells obtained in our previous study. For target gene sequencing, 76 genes were selected based on previous genomic analyses for ovarian endometriosis, normal endometrium, endometriosis-related ovarian cancer and endometrial cancer. MAIN RESULTS AND THE ROLE OF CHANCE Stromal samples in ovarian endometrioma and normal endometrium harbor somatic mutations (18 mutations in 11 endometriosis samples and 16 mutations in 10 normal endometrial samples) but did not share any mutations with paired epithelial samples. The mutant allele frequency of stromal samples was significantly lower than that of epithelial samples in ovarian endometrioma (P = 6.0 × 10-11) and normal endometrium (P = 1.4 × 10-7). LIMITATIONS, REASONS FOR CAUTION The number of genes evaluated in the mutational analysis was limited. Additionally, the functional roles of somatic mutations in stromal cells remain unclear. WIDER IMPLICATIONS OF THE FINDINGS Different mutation profiles between paired epithelial and stromal cells in both ovarian endometrioma and normal endometrium suggest that origins of epithelial and stromal cells would be independent of each other in both normal endometrium and ovarian endometrioma; however, the theory of epithelial-mesenchymal transition is proposed in ovarian endometrioma. STUDY FUNDING/COMPETING INTEREST(S) This work was supported in part by the Japan Society for the Promotion of Science KAKENHI grant number JP15H02373 (Grant-in-Aid for Scientific Research A for I.I.), JP16H06267 (Grant-in-Aid for Young Scientists A for K.Y.), JP17K08688 (Grant-in-Aid for Scientific Research C for H.N.) and JP16H06279 (Grant-in-Aid for Scientific Research on Innovative Areas—Platforms for Advanced Technologies and Research Resources for H.N. and K.Y). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER Not applicable.

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