Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment

Abstract

Epithelial ovarian cancer is a highly heterogeneous disease characterized by multiple histological subtypes. Molecular diversity has been shown to occur within specific histological subtypes of epithelial ovarian cancer, between different tumors of an individual patient, as well as within individual tumors. Recent advances in the molecular characterization of epithelial ovarian cancer tumors have provided the basis for a simplified classification scheme in which these cancers are classified as either type I or type II tumors, and these two categories have implications regarding disease pathogenesis and prognosis. Molecular analyses, primarily based on next-generation sequencing, otherwise known as high-throughput sequencing, are allowing for further refinement of ovarian cancer classification, facilitating the elucidation of the site(s) of precursor lesions of high-grade serous ovarian cancer, and providing insight into the processes of clonal selection and evolution that may be associated with development of chemoresistance. Potential therapeutic targets have been identified from recent molecular profiling studies of these tumors, and the effectiveness and safety of a number of specific targeted therapies have been evaluated or are currently being studied for the treatment of women with this disease.

Keywords: epithelial ovarian cancer; high throughput sequencing; next-generation sequencing.

Figure 1

(A) Histological subtypes of ovarian cancer; and (B) traditional epithelial ovarian cancer classification paradigm based on tumor histology and grade (prevalence of histological subtypes from: McCluggage et al. [8]).

Figure 2

(A) Histological subtypes of ovarian cancer; and (B) widely accepted epithelial ovarian cancer classification paradigm based on clinicopathologic and molecular evidence that type I and type II tumors develop through different pathways (Kurman et al. [18]). * Indicates rare tumor; ^† Mucinous and malignant Brenner tumors are considered to be possible exceptions that may arise from transitional cells at or close to the junction of the fallopian tube and the peritoneum.

Figure 3

Molecular targets in ovarian cancer treatment; * Indicates inactive (phosphorylated) form of cyclin-dependent kinase 1; Green arrows indicate stimulation while the red lines indicate inhibition; 4E-BP1: eukaryotic translation initiation factor 4E-binding protein 1; AKT: protein kinase B; CCNB: cyclin B; CDK1: cyclin dependent kinase-1; ERK: extracellular signal-related kinase; HER2: human epidermal growth factor receptor 2; MEK: MAPK/ERK kinase; mTORC1: mammalian target of rapamycin complex 1; mTORC2: mammalian target of rapamycin complex 2; PDK1: phosphoinositide-dependent kinase-1; PI3K: phosphoinositol 3-kinase; RAF: a serine/threonine-specific kinase; RAS: a member of a specific GTPase superfamily; Rheb: Ras homolog enriched in brain protein; S6K1: S6 kinase beta-1; TSC1/2: tuberous sclerosis proteins 1 and 2; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor.