Iatrogenic endometriosis harbors somatic cancer-driver mutations

Objectives:

Endometriosis is a common gynecological disease and precursor of clear cell and endometrioid ovarian carcinomas. We recently demonstrated that one form of endometriosis with little malignant potential, deep infiltrating endometriosis (DE), harbours recurrent somatic cancer-driver mutations. The prevalence of these mutations in other forms of endometriosis is not known. We sought to investigate this by examining other forms of endometriosis unlikely to undergo transformation. Particularly, we examined an iatrogenic form of endometriosis (incisional endometriosis; IE) where the uterine origin of cells is well accepted.

Materials and methods:

Endometriosis specimens were macrodissected from archival tissue collected from 40 women with IE and 36 women with DE. A hypersensitive cancer hotspot sequencing panel was used to identify mutations, which were validated using droplet digital PCR. PTEN and ARID1A immunohistochemistry were performed as surrogates for somatic events resulting in functional loss of respective proteins.

Results:

Somatic cancer-driver events were detected in 27.5% IE cases and 38.9% DE cases, including hotspot mutations in KRAS, ERBB2, PIK3CA, and CTNNB1. Heterogeneous PTEN loss occurred at similar rates in IE and DE (6/40 versus 5/36 respectively), whereas ARID1A loss only occurred in one DE case.

Conclusions:

Despite differing mechanisms of dissemination, somatic cancer-driver events are a common feature of IE and DE. These alterations affected components of the MAPK/RAS or PI3K-Akt-mTOR pathways, which may be important in the growth and survival of endometriosis ectopically. Examination of similar somatic events in eutopic endometrium and other forms of endometriosis, in particular endometriomas (commonly linked to malignancy) are warranted.