Endometriosis-Associated Ovarian Cancer: From Molecular Pathologies to Clinical Relevance

Abstract

Endometriosis is a chronic condition affecting reproductive-aged women, characterized by the growth of ectopic endometrial tissue. Despite being benign, endometriosis is associated with an increased risk of certain cancers, including endometriosis-associated ovarian cancer (EAOC). Ovarian cancer is rare, but more common in women with endometriosis, particularly endometrioid and clear-cell carcinomas. Factors such as hormonal imbalance, reproductive history, environmental exposures, and genetic predisposition contribute to the malignant transformation of endometriosis. Thus, understanding potential risk factors causing malignancy is crucial. Over the past few decades, various genetic mutations, microRNAs, as well as tumor microenvironmental factors have been identified, impacting pathways like PI3K/AKT/mTOR, DNA repair mechanisms, oxidative stress, and inflammation. Thus, this review aims to summarize molecular studies involved in EAOC pathogenesis as potential therapeutic targets. However, further research is needed to better understand the molecular and environmental factors driving EAOC development, to target the susceptibility of endometriotic lesions to malignant progression, and to identify effective therapeutic strategies.

Keywords: EAOC; endometriosis; ovarian cancer.

Figure 1

Molecular factors involved in the malignant transformation of endometrioma to endometriosis-associated ovarian cancer (EAOC). Through retrograde menstruation, endometrial tissue grows outside the uterus in ectopic locations including the ovaries. Hereby, several genetic alterations, microRNAs, local estrogen levels, and oxidative stress contribute to the malignant transformation of benign endometrial lesions to tumor progression. Common genetic mutations accumulating during the growth process affect the function of the proto-oncogene K-Ras (Kirsten rat sarcoma virus), the tumor suppressor gene P53 (TP53), the catalytic subunit alpha (PIK3CA) of the phosphatidylinositol 3-kinase (PI3K), as well as negative regulators of the PI3K/AKT/mTOR pathway, including the phosphatase and tensin homolog (PTEN) and a regulatory subunit of protein phosphatase 2 (PP2A) (encoded by the PPP2R1A gene). Furthermore, the AT-rich interactive domain-containing protein 1A (ARID1A) is frequently mutated, leading to the altered function of the mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) complex, a subfamily of ATP-dependent chromatin remodeling complexes. Altogether, those mutated genes are mainly responsible for DNA damage repair, the regulation of apoptosis, protein synthesis, cell cycle control, proliferation, survival, and growth. Therefore, other signaling pathways such as the Wnt pathway (e.g., Wnt protein, lipoprotein receptor-related protein (LRP), T-cell factor/lymphoid enhancer factor, beta-catenin, but also its destruction complex [axin, adenomatosis polyposis coli (APC), glycogen synthase kinase 3 (GSK3) and casein kinase 1α (CK1α)]) and Notch pathways (neurogenic locus notch homolog protein-induced liberation of N-formylmaleamic acid amidohydrolase) may also be related to the development of EAOC. Alongside tumor-intrinsic genetic factors, microRNAs (miRNAs) serve as crucial post-transcriptional regulators of gene expression, exhibiting complex dysregulation in various human cancers, with the differential expression of specific families like miR-200, let-7, and miR-31 influencing epithelial-to-mesenchymal transition, oncogenicity, and angiogenesis. Furthermore, estrogen promotes endometriotic cell proliferation through various signaling pathways, while an imbalance favoring estrogen receptor (ER)-alpha dominance or loss of ER-beta contributes to carcinogenesis via an estrogen-responsive element (ERE)- or transcription factor (TF) response element (TFRE)-mediated gene transcription. In addition, estradiol binds to the G protein-coupled estrogen receptor 1 (GPER1 or GPR30), leading to the activation of the cAMP/PKA (protein kinase A)/CREB (cAMP response element-binding protein) pathway. Finally, oxidative stress plays a pivotal role in shaping EAOC by inducing DNA damage, inflammation, and aberrant cellular signaling and disrupting antioxidant defenses. [Figure created with BioRender].

Figure 2

Diagnostic and therapeutic algorithm for endometriosis and endometriosis-associated ovarian cancer (EAOC). For further detailed information, see ESHRE guidelines.