An Integrated Clinical-Genomics Approach Identifies a Candidate Multi-Analyte Blood Test for Serous Ovarian Carcinoma

Abstract

Purpose: Cancer of the ovary confers the worst prognosis among women with gynecologic malignancies, underscoring the need to develop new biomarkers for detection of early disease, particularly those that can be readily monitored in the blood. Experimental Design: We developed an algorithm to identify secreted proteins encoded among f22,500 genes on commercial oligonucleotide arrays and applied it to gene expression profiles of 67 stage I to IV serous papillary carcinomas and 9 crudely enriched normal ovarian tissues, to identify putative diagnostic markers. ELISAs were used to validate increased levels of secreted proteins in patient sera encoded by genes with differentially high expression. Results: We identified 275 genes predicted to encode secreted proteins with increased/ decreased expression in ovarian cancers (<0.5-or >2-fold, P < 0.001). The serum levels of four of these proteins (matrix metalloproteinase-7, osteopontin, secretory leukoprotease inhibitor, and kallikrein 10) were significantly elevated in a series of 67 independent patients with serous ovarian carcinomas compared with 67 healthy controls (P < 0.001, Wilcoxon rank sum test). Optimized support vector machine classifiers with as few as two of these markers (osteopontin or kallikrein 10/matrix metalloproteinase-7) in combination with CA-125 yielded sensitivity and specificity values ranging from 96% to 98.7% and 99.7% to 100%, respectively, with the ability to discern early-stage disease from normal, healthy controls. Conclusions: Our data suggest that this assay combination warrants further investigation as a multi-analyte diagnostic test for serous ovarian adenocarcinoma.

Clinical utility of circulating matrix metalloproteinase-7 (MMP-7), CC chemokine ligand 18 (CCL18) and CC chemokine ligand 11 (CCL11) as markers for diagnosis of epithelial ovarian cancer

“…The diagnostic significance of CA 125 is well recognized in patients with EOC [4,5,7,8]. Serum MMP-7 was previously reported to be increased in patients with EOC compared to healthy controls; however, it was noticed that such study was limited CA 125, MMP-7 and CCL18 were significantly increased in patients with benign ovarian lesions compared to controls (P \ 0.001, P \ 0.001, P = 0.002, respectively) CCL11 was significantly decreased in ovarian cancer patients compared to either controls (P = 0.010) or patients with benign ovarian lesions (P = 0.037) * P value is significant to serous ovarian carcinoma [29]. MMP-7 can promote cancer invasion by proteolytic cleavage of the ECM substrates [14].…”

Confounding Effects of Hormone Replacement Therapy in Protein Biomarker Studies

“…In addition to proteins that have been assayed in the blood as potential ovarian cancer biomarkers, we investigated proteins that were recently described as potential markers by Kulasingam et al (21) based on their proteomic identification in ovarian cancer cell lines (6, 22), ascites (23, 24), and tumor tissue (25), and oligonucleotide microarray experiments (26). Table 2 presents proteins that were identified in at least 3 of 6 ovarian cancer proteomic and/or transcriptomic studies for which data for the effects of HRT on their levels was available.…”

The role of p53 as a surrogate marker for chemotherapeutical responsiveness in ovarian cancer

“…In LMP tumors and well-differentiated OCs, RAS mutations are frequently observed, whereas only a few such mutations have been found in G2/3 OCs (Shih and Kurman 2004;Dehari et al 2007). Our group (Meinhold-Heerlein et al 2007) recently demonstrated by gene expression profiling that LMP/G1 differentiated OCs clustered together and G2/ 3 OCs shared similarities in gene expression profiles. On the contrary, p53 has been shown to be frequently mutated in moderately and poorly differentiated OC (Salani et al 2008).…”