Molecular Management of High-Grade Serous Ovarian Carcinoma

Abstract

High-grade serous ovarian carcinoma (HGSOC) represents the most common form of epithelial ovarian carcinoma. The absence of specific symptoms leads to late-stage diagnosis, making HGSOC one of the gynecological cancers with the worst prognosis. The cellular origin of HGSOC and the role of reproductive hormones, genetic traits (such as alterations in P53 and DNA-repair mechanisms), chromosomal instability, or dysregulation of crucial signaling pathways have been considered when evaluating prognosis and response to therapy in HGSOC patients. However, the detection of HGSOC is still based on traditional methods such as carbohydrate antigen 125 (CA125) detection and ultrasound, and the combined use of these methods has yet to support significant reductions in overall mortality rates. The current paradigm for HGSOC management has moved towards early diagnosis via the non-invasive detection of molecular markers through liquid biopsies. This review presents an integrated view of the relevant cellular and molecular aspects involved in the etiopathogenesis of HGSOC and brings together studies that consider new horizons for the possible early detection of this gynecological cancer.

Keywords: early diagnosis; high-grade serous ovarian carcinoma; liquid biopsy; molecular biomarkers; ovarian cancer.

Figure 1

Two main theories of the cellular origin of high-grade serous ovarian carcinoma (HGSOC): (1) Reactive oxygen species (ROS), inflammatory molecules (IL-6, IL-8, and cytokines), and hormones (FSH, LH, and estrogens) released during ovulation induce constant tissue damage and repair cycles, leading to HGSOC in the ovarian epithelial surface (OSE), which might also be triggered by the formation of cortical inclusion cysts (CICs). (2) Alternatively, malignant transformation triggered by the pro-inflammatory and pro-oxidative environment generates serous tubular intra-epithelial carcinoma (STIC) lesions in the fallopian tube epithelium (FTE), which give rise to HGSOC after migrating and invaginating in the OSE as CICs.

Figure 2

Frequently altered signaling pathways in HGSOC: Different mutations and genomic aberrations affect the PI3K/Akt, Ras/Raf, Rb, FOXM1, and Notch pathways, resulting in the dysregulation of downstream target gene expression, which can subsequently promote genomic instability, cell-cycle dysregulation, enhanced cell proliferation, cancer stemness, and tumor progression.

Figure 3

Liquid biopsy strategies for the early detection of HGSOC: Liquid biopsies rely on isolating CTCs, ctDNA, ctRNAs, or exosomes released by tumors that enter the bloodstream. Different analytical techniques support the identification of putative biomarkers for the early diagnosis of HGSOC.