High-throughput sequencing technologies revolutionized medical genomic research, which enabled us to proceed “sequence-based medicine”. Endometriosis is a common disease affecting about 8 % of women, also might develop ovarian cancer in some cases. 

Retrograde menstruation is well-known as the origin of endometriosis but there is no molecular-based supports. We focused on somatic mutation profiles in both endometriotic and normal uterine endometrial epithelium samples to prove the retrograde menstruation hypothesis leading to the pathogenesis of endometriosis. We analyzed whole-exome and target-gene sequencing data derived from 107 ovarian endometriotic epithelium and 82 normal uterine endometrial epithelium samples. 

Although common cancer-associated mutations were detected in both tissues, their distributions of mutant allele frequency (MAF) in endometriotic epithelium were significantly higher than in normal endometrium. Particularly, steep increase in MAF of mutations on KRAS in endometriotic epithelium was observed suggesting that endometrial tissues harboring KRAS mutations were transported in a retrograde direction to the ovarian surface, where the specific KRAS mutations gave them selective advantages at this and other ectopic sites, leading to the development of endometriosis and widespread distribution of the clone across the endometriotic lesions.

In particular case, we conducted exome sequencing for a set of samples including normal uterine endometrium, distant endometriosis, atypical endometriosis, stromal cells in cancer, and ovarian clear cell cancer (OCCC) tissues from a 56-year-old patient. We analyzed the mutant allele frequencies of somatic mutations in cancer-driver genes present in each of the samples, which enabled us the identification of a sequential genomic footprint that is shared in some of the tissues.

Furthermore, we recognized a directional evolution pattern that denotes the importance of the retrograde menstruation theory in the development of endometriosis, and subsequently, its evolution into OCCC.

In conclusion, our genomic studies disentangled the riddle of the origin of endometriosis supporting Sampson’s retrograde hypothesis with a century-old history.