Background: Endometriosis is a common reproductive disease with a heterogeneous presentation. Classification attempts have thus far not offered insight into its cause or its symptoms. Endometriosis may result from the migration of shed endometrium to the peritoneal cavity. However, there are cases reported in girls without uteruses and men. While a non-retrograde menstruation origin of ectopic tissue is certain in these cases, we propose using DNA methylation age (DNAm age) to distinguish between retrograde and non-retrograde etiologies. Methods: Using publicly available DNA methylation data and Horvath's pan-tissue epigenetic clock, we compared DNAm age and epigenetic age acceleration (EAA) of ectopic lesions to eutopic endometrium of diseased and control endometrium. We examined EAA in cancer metastasis and teratomas to control for migration and developmental origin. Results: Disease status does not change DNAm age of eutopic endometrium, but the effect of ectopic status was profound: -16.88 years (p = 4.82 x 10-7). There were no differences between EAA of primary/metastatic tumor pairs, suggesting that the observed effect is not due to migration. Immature or mature teratoma compartments decreased DNAm age by 9.44 and 7.40 years respectively, suggesting that developmental state correlates with DNAm age. Conclusions: Ectopic endometriotic tissue exhibits decelerated DNAm age, similar to that observed in teratomas composed of multipotent tissue. The migration process does not change DNAm age and eutopic endometrium is concordant with chronological age regardless of disease status. We conclude that DNAm age of ectopic lesions can classify endometriosis into distinct subtypes that may be clinically relevant.

Epigenetic age provides insight into tissue origin in endometriosis