A serum based analysis of ovarian epithelial tumorigenesis

Abstract

Objectives: Ovarian epithelial carcinoma can be subdivided into separate histological subtypes including clear cell, endometrioid, mucinous, and serous. These carcinoma subtypes may represent distinctive pathways of tumorigenesis and disease development. This distinction could potentially be reflected in the levels of tumor produced factors that enter into the circulation and serve as biomarkers of malignant growth. Here, we analyze levels of circulating biomarkers from a diverse set of patients diagnosed with ovarian carcinoma to identify biomarker trends and relationships associated with distinct carcinoma histotypes and divergent tumorigenic pathways.

Methods: We utilize multiplexed bead-based immunoassays to measure serum levels of a diverse array of fifty-eight biomarkers from the sera of patients diagnosed with various histological subtypes of ovarian carcinoma and benign lesions. The biomarkers studied include cancer antigens, oncogenes, cytokines, chemokines, receptors, growth and angiogenic factors, proteases, hormones, and apoptosis and adhesion related molecules. Levels of each biomarker are compared statistically across carcinoma subtypes as well as with benign cases.

Results: A total of 21 serum biomarkers differ significantly between patients diagnosed with ovarian carcinomas and benign cases. Nine of these biomarkers are specific for carcinomas identified as clear cell, endometrioid, or mucinous in histology, while two biomarkers are specific for the serous histology. In a direct comparison of the histology groups, ten biomarkers are found to be subtype specific. Identified biomarkers include traditional and emerging tumor markers, cytokines and receptors, hormones, and adhesion- and metastasis-related proteins.

Conclusions: We demonstrate here that the divergent histology-based tumorigenic pathways proposed for ovarian epithelial carcinomas are associated with distinct profiles of circulating biomarkers. Continued investigation into the relationships between these factors should reveal new insights into the complex mechanisms underlying ovarian epithelial tumorigenesis.

Figure 1. Serum Biomarkers Significant Across Ovarian Epithelial Carcinoma Subtypes

Findings presented in Table 3 are summarized. Listed biomarkers were found to differ significantly between comparison groups. Arrow preceding each biomarker name indicates increased or decreased serum concentrations in the cancer group. A. Comparison between benign cases and ovarian cancer subtypes. B. Comparison between clear cell, endometrial, and mucinous (CEM) carcinomas and serous carcinomas.

Figure 2. Ingenuity Pathway Analysis of Identified Serum Biomarkers and Reported Molecular Alterations

The Ingenuity Pathway Analysis software package (Ingenuity Systems Inc., Redwood City, CA) was used to identify relationships between identified serum biomarkers and genetic markers associated with ovarian carcinoma subtypes. A. Interactions identified between CEM carcinoma associated serum biomarkers and the following genes: BRAF, KRAS, CTNNBI, PTEN, MAP3K, and PI3K. B. Interactions identified between serous carcinoma associated serum biomarkers and the following genes: AKT2, APOE2, BCL2, HLA-G, MK167, TP53, and WT1. Biomarker outlines: green - increased in the serum of cancer patients, red – decreased in the serum of cancer patients. Interaction labels: A – activation, E – expression, PD – protein-DNA interaction, T – transcription, PP – protein-protein interaction, LO – localization, RB – regulation of binding, solid line – direct relationship, dashed line – indirect relationship.