Endometriosis-associated ovarian carcinomas: insights into pathogenesis, diagnostics, and therapeutic targets—a narrative review

Abstract

Endometriosis is a benign gynecologic condition affecting up to one woman out of ten of reproductive age. It is defined by the presence of endometrial-like tissue in localizations outside of the uterine cavity. It often causes symptoms such as chronic pain, most frequently associated with the menstrual cycle, and infertility, but may also be oligo-or asymptomatic. There is evidence that some ovarian carcinoma (OC) histotypes, mainly the ovarian clear cell (OCCC) and endometrioid (EnOC) carcinoma, may arise from endometriosis. The most frequent genomic alterations in these carcinomas are mutations in the AT-rich interacting domain containing protein 1A (ARID1A) gene, a subunit of the SWI/SNF chromatin remodeling complex, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which frequently co-occur. In ARID1A deficient cancers preclinical experimental data suggest different targetable mechanisms including epigenetic regulation, cell cycle, genomic instability, the PI3K/AKT/mTOR pathway, inflammatory pathways, immune modulation, or metabolic alterations as potential precision oncology approaches. Most of these strategies are relying on the concept of synthetic lethality in which tumors deficient in ARID1A are more sensitive to the different compounds. Some of these approaches are currently being or have recently been investigated in early clinical trials. The remarkably frequent occurrence of these mutations in endometriosisassociated ovarian cancer, the occurrence in a relatively young population, and the high proportion of platinumresistant disease certainly warrants further investigation of precision oncology opportunities in this population. Furthermore, advanced knowledge about oncogenic mutations involved in endometriosis-associated ovarian carcinomas may be potentially useful for early cancer detection. However, this approach may be complicated by the frequent occurrence of somatic mutations in benign endometriotic tissue as recent studies suggest. In this narrative review of the current literature, we will discuss the data available on endometriosis-associated ovarian carcinoma, with special emphasis on epidemiology, diagnosis and molecular changes that could have therapeutic implications and clinical applicability in the future.

Epithelial Cells of Deep Infiltrating Endometriosis Harbor Mutations in Cancer Driver Genes

“…Attempts to identify somatic mutations that lead to the development of endometriotic lesions proved that some cancer-driving genes are more frequently mutated in ovarian endometriosis [17,18]. Mutations in these genes: ARID1A, PIK3CA, KRAS, are also found in ovarian cancer that is associated with endometriosis [19]. However, the same genes have been found to be mutated in eutopic endometrium in women without endometriosis, leaving the question about their pathogenicity still unanswered.…”

Transcriptome Analyses Identify Potential Key microRNAs and Their Target Genes Contributing to Ovarian Reserve

“…Especially, POI-related gene families and pathways, such as the Fas ligand ( FasL )-Fas pathway, nuclear factor-kappa B ( NF-κB ), inhibitory kappa B α ( IκBα ), interleukin-1 receptor-associated kinase ( IRAK1 ), and tumor necrosis factor receptor-associated factor 6 ( TRAF6 ), have been reported in humans [ 41 , 42 , 43 ].…”

Correlation of Clinicopathological and Prognostic Characteristics between Endometriosis-Associated and Primary Ovarian Cancer

“…Several recent studies have shown that endometriosis patients have signi cantly increased risk of ovarian cancer [12]. As a precancerous lesion, endometriosis is closely related to ovarian clear cell and endometrioid carcinomas.…”