Cancer-Associated Mutations in Endometriosis without Cancer

Abstract

BACKGROUND Endometriosis, defined as the presence of ectopic endometrial stroma and epithelium, affects approximately 10% of reproductive-age women and can cause pelvic pain and infertility. Endometriotic lesions are considered to be benign inflammatory lesions but have cancerlike features such as local invasion and resistance to apoptosis. METHODS We analyzed deeply infiltrating endometriotic lesions from 27 patients by means of exomewide sequencing (24 patients) or cancer-driver targeted sequencing (3 patients). Mutations were validated with the use of digital genomic methods in micro-dissected epithelium and stroma. Epithelial and stromal components of lesions from an additional 12 patients were analyzed by means of a droplet digital polymerase-chain-reaction (PCR) assay for recurrent activating KRAS mutations. RESULTS Exome sequencing revealed somatic mutations in 19 of 24 patients (79%). Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis. The likelihood of driver genes being affected at this rate in the absence of selection was estimated at P = 0.001 (binomial test). Targeted sequencing and a droplet digital PCR assay identified KRAS mutations in 2 of 3 patients and 3 of 12 patients, respectively, with mutations in the epithelium but not the stroma. One patient harbored two different KRAS mutations, c.35G→T and c.35G→C, and another carried identical KRAS c.35G→A mutations in three distinct lesions. CONCLUSIONS We found that lesions in deep infiltrating endometriosis, which are associated with virtually no risk of malignant transformation, harbor somatic cancer driver mutations. Ten of 39 deep infiltrating lesions (26%) carried driver mutations; all the tested somatic mutations appeared to be confined to the epithelial compartment of endometriotic lesions.

Chronic Niche Inflammation in Endometriosis-Associated Infertility: Current Understanding and Future Therapeutic Strategies

“…Although further research is required for validation, one plausible explanation for this is that ectopic lesions may be derived from two cellular origins, namely initial establishment of the epithelial compartment by endometrial progenitor cells harboring cancer driver mutation, followed by stromal compartment establishment by BMDCs [194]. …”

Role of endometriosis as a prognostic factor for post‑progression survival in ovarian clear cell carcinoma

“…Short PPS in CCC could have led to shorter OS in CCC cases, especially in EM-group patients. Although genetic difference in the tissue specimens was not evaluated in the present study, a report suggested that some patients carried driver mutations in ARID1A, PIK3CA, KRAS genes in benign deep infiltrating endometriosis (19). It is speculated that tumor samples of EM-group had potentially aggressive phenotype compared with non-EM group tumors.…”

“…Primary therapy using anti-cancer agents might alter genetic profile in CCC tumors, and cause refractory phenotype after recurrence. A report suggested CCC patients with Met gene amplification showed chemoresistant phenotype and worse prognosis (19). Thus, the alteration of genetic profiles affected by primary therapy might influence PPS in the patients with CCC.…”

Absence of KRAS hotspot mutations in endometriosis of Korean patients

“…Although the exact cause of endometriosis remains unknown, many theories have been presented, including retrograde menstruation (implantation) and stem cell theories . Endometriosis includes three subtypes: superficial peritoneal endometriosis, ovarian endometriosis, and deep infiltrating endometriosis (DIE), although there is a large degree of overlap between these three categories, and they are not well defined. DIE is a highly invasive form of endometriosis that is often characterised by nodules with painful symptoms .…”