Epithelial Mutations in Endometriosis

Link Between Endometriosis and Epithelial Ovarian Cancer

Key Points

Highlight:

• Dr. Bulun's group discuss in this review the significance of mutations in epithelial cells in endometriosis in general and a plausible link between epithelial mutations in endometriosis and ovarian cancer initiation.

Background:

• Epidemiologic and histopathologic associations between endometriosis and epithelial ovarian cancer have been reported.
• However, the underlying molecular and cellular mechanisms are not well understood.
• In this review, Dr. Matei group from Northwestern University discuss the implications of recent genetic breakthroughs linking endometriosis and ovarian cancer.

Key points:

• The recent sequencing studies demonstrated that driver mutations (such as PIK3CA, KRAS, ARID1A) have been found in the epithelium of intrauterine endometrial tissue, ovarian and extra-ovarian pelvic endometriosis tissue, ovarian cancers associated with endometriosis, and other epithelial ovarian cancers.
• It is plausible that endometriosis involves excessive retrograde menstruation that carries cancer progenitor cells into the ovarian parenchyma.
• In case these mutated cells are deposited in extra-ovarian sites, they do not seem to initiate a malignant process.
• On the other hand, if they populate an ovarian inclusion cyst, these mutations may drive the development of various types of ovarian cancers, including clear cell and endometrioid cell cancers.
• In contrast to epithelial cells, the endometriotic stromal cells of extra-ovarian or ovarian endometriosis seem to lack any classical mutations.
• However, these stromal cells are progesterone-resistant and induce an inflammatory environment driven by estrogen via estrogen receptor-b, which enhance proliferation in neighboring epithelial cells.
• Massive estrogen in the ovary may also exert an additional genotoxic effect on DNA in initially mutated endometriotic epithelial cells in an ovarian endometrioma, which may initiate epithelial ovarian cancer.

Lay Summary

A substantial body of epidemiologic evidence suggests a link between endometriosis and epithelial ovarian cancer, but a plausible underlying mechanism has remained elusive. Here, Dr. Bulun group from Northwestern University provide a focused review of the literature and discuss the implications of recent genetic breakthroughs linking endometriosis and ovarian cancer.

The recent sequencing studies demonstrated that driver mutations in PIK3CA, KRAS, ARID1A, and other genes have been found in the epithelium of intrauterine endometrial tissue, ovarian and extra-ovarian pelvic endometriosis tissue, ovarian cancers associated with endometriosis, and other epithelial ovarian cancers.

Considering these findings, it is plausible that endometriosis involves excessive retrograde menstruation that carries cancer progenitor cells into the ovarian parenchyma. In case these mutated cells are deposited in extra-ovarian sites, they do not seem to initiate a malignant process. On the other hand, if they populate an ovarian inclusion cyst, these mutations may drive the development of various types of ovarian cancers, including clear cell and endometrioid cell cancers.

Unlike epithelial cells, endometriotic stromal cells are mutation free but contain widespread epigenetic defects that alter gene expression and induce a progesterone-resistant and intensely inflammatory environment, driven by estrogen via estrogen receptor-b. This might enhance the proliferation of neighboring epithelial cells. Massive estrogen in the ovary may also exert an additional genotoxic effect on DNA in initially mutated endometriotic epithelial cells in an ovarian endometrioma, which may initiate epithelial ovarian cancer.

Research Source: https://www.ncbi.nlm.nih.gov/pubmed/30657901