Pathogenesis and heterogeneity of ovarian cancer

Abstract

Purpose of reviewThe most common type of ovarian cancer, high-grade serous ovarian carcinoma (HGSOC), was originally thought to develop from the ovarian surface epithelium. However, recent data suggest that the cells that undergo neoplastic transformation and give rise to the majority of HGSOC are from the fallopian tube. This development has impacted both translational research and clinical practice, revealing new opportunities for early detection, prevention, and treatment of ovarian cancer.Recent findingsGenomic studies indicate that approximately 50% of HGSOC are characterized by mutations in genes involved in the homologous recombination pathway of DNA repair, especially BRCA1 and BRCA2. Clinical trials have demonstrated successful treatment of homologous recombination-defective cancers with poly-ribose polymerase inhibitors through synthetic lethality. Recently, amplification of CCNE1 was found to be another major factor in HGSOC tumorigenesis, accounting for approximately 20% of all cases. Interestingly, amplification of CCNE1 and mutation of homologous recombination repair genes are mutually exclusive in HGSOC.SummaryThe fallopian tube secretory cell is the cell of origin for the majority of ovarian cancers. Although it remains unclear what triggers neoplastic transformation of these cells, certain tumors exhibit loss of BRCA function or amplification of CCNE1. These alterations represent unique therapeutic opportunities in ovarian cancer.

Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C

“…Expression of the UBB gene is otherwise best described as a housekeeping gene; when examined across 30 tissue types, it is less variable than GAPDH, and there is no tissue in which UBB appears transcriptionally inactive (Supplemental Figure 1B). These results do not provide insight to help explain the incidence of UBB silencing in gynecological tissues and leaves open the possibility that UBB repression is a consequence of alterations in ovarian surface and fallopian epithelium (47)(48)(49). All 3 tumor types with a high incidence of UBB silencing are derived from Müllerian epithelium, a finding that should prompt follow-up studies to consider UBB expression and promoter methylation status in these cells (50).…”

Ginsenoside 20(S)-Rg3 Prevents PKM2-Targeting miR-324-5p from H19 Sponging to Antagonize the Warburg Effect in Ovarian Cancer Cells

“…The 5-year survival has long been less than 50% in most countries [2]. Chemotherapy is the main adjuvant therapy for EOC, however, its efficacy is frequently impaired by occurrence of chemoresistance and adverse reaction [3]. Development of novel therapeutics is an important strategy to improve the prognosis of EOC patients.…”

Conceptual frameworks of synthetic lethality in clear cell carcinoma of the ovary (Review)

“…MYC-amplified cancer cells have been associated with elevated levels of DNA replication stress (12). Amplification of CCNE1 and mutation of BRCA1/2 genes are reportedly mutually exclusive in HGSC, suggesting that CCNE1 induces synthetic lethality in BRCA1/2-mutated cells (3).…”

“…HGSC was originally thought to develop from the ovarian surface epithelium and/or ovarian inclusion cysts (2). However, recent research has contradicted this and suggests that the majority of HGSC develops from fallopian tube fimbrial epithelium (3).…”

“…Specific inhibitors of the cancer driver genes or oncogenes may contribute to development of idiosyncratic toxicity (23). An example of synthetic lethality is PARP inhibition in BRCA1/2-deficient ovarian and/or breast cancer types (3,24,25). Since homologous recombination-associated genes, including BRCA1, BRCA2, RAD51 recombinase (RAD51), Fanconi anemia complementation group and p53 genes, are essential for DNA damage repair and survival, cancer cells may use an alternative approach (non-oncogenes) and become dependent upon the parallel route (26).…”