Pathogenesis and heterogeneity of ovarian cancer

Abstract

Purpose of review: The 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 findings: Genomic 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.

Summary: The 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.

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FIGURE 1

Pathological and genomic features of high-grade serous ovarian carcinomas (HGSOCs). The majority of HGSOCs emerge from the fallopian tube epithelium through a series of precursor lesions that target the secretory cell. Normal fallopian tube epithelium contains both secretory and ciliated cells and is typically immunonegative for p53. The benign ‘p53 signature’ is composed entirely of secretory cells that exhibit strong p53 expression and evidence of DNA damage but are not proliferative. With progression to a serous tubal intraepithelial carcinoma or ‘STIC’, there is acquisition of nuclear pleomorphism, mitoses, and loss of polarity. Invasive HGSOC shares all these properties and clinical symptoms typically emerge with advanced disease [22].

FIGURE 2

Amplification of CCNE1 across human cancers. The cbioportal (http://www.cbioportal.org) was queried for ‘CCNE1: AMP’ and the resulting bar graph was limited to tumors with at least 4% amplification.