Genetic Studies Provide Possible Mechanistic Link Between Endometriosis and Ovarian Cancer

Genetic breakthroughs from three recent whole-exome sequencing studies of endometrial and endometriotic epithelial cells provided some unexpected findings linking endometriosis and ovarian cancer, according to a paper recently published in Endocrinology.

The paper, by Serdar E. Bulun, MD, of the Feinberg School of Medicine at Northwestern University in Chicago, notes that while associations between endometriosis and epithelial ovarian cancer have been reported, the mechanisms haven’t been well understood.

In this paper, the researchers review and discuss the results from three exome-wide sequencing studies that demonstrated commonly occurring epithelial mutations in PIK3CA and ARID1A in endometriosis that are uniquely shared with clear cell and endometrioid ovarian epithelial cancers. These studies also showed mutations in KRAS that are commonly observed in low-grade serous ovarian cancers are uniquely observed in the epithelial cells of extraovarian endometriotic lesions. “As a further twist,” the authors write, “the epithelial cells (a.k.a., glandular cells) in histologically and clinically normal endometrial tissue harbors many driver mutations (e.g.,PIK3CA, KRAS) with comparable mutant allele frequencies to those found in ovarian endometriotic epithelium.”

The authors go on to write that the stromal cells seem to lack any mutations that would alter protein function, but these endometriotic stromal cells contain numerous epigenetic defects that favor overproduction of E2 and overexpression of the steroid receptor ERβ that mediates an intense and E2-induced inflammatory process involving overproduction of cytokines and prostaglandins.

These findings raised some intriguing questions, the authors write, so they set out to provide answers and a plausible link between epithelial mutations in endometriosis and ovarian cancer initiation. Epithelial mutations in endometriosis driving ovarian cancer makes sense because endometriosis occurs as a result of retrograde menstruation and these cells can become implanted in ovarian inclusion cysts or extraovarian peritoneal or subperitoneal sites.

As for the non-mutated stromal cells, their widespread epigenetic defects alter gene expression and induce an inflammatory environment. “In addition, massively high concentrations of estrogen in the ovary may exert an additional and direct genotoxic effect on DNA and cause accumulation of additional mutations and malignant transformation in initially mutated endometriotic epithelial cells in an ovarian endometrioma, which may initiate epithelial ovarian cancer,” the authors write.

The authors point out that this focused review only attempts to provide some initial thoughts on the questions the findings of these genetic studies raised. “Developing novel disease models and paradigm-shifting approaches will be essential to providing definitive answers to these challenging questions,” they conclude.

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