Abstract
BackgroundOvarian cancer (OVC) is the deadliest of all gynecologic cancers, primarily as a consequence of asymptomatic progression. The complex nature of OVC creates challenges for early detection, and there is a lack of specific and sensitive biomarkers suitable for screening and detecting early stage OVC.MethodsPotential OVC biomarkers were identified by bioinformatic analysis. Candidates were further screened for differential expression in a library of OVC cell lines. OVC-specific overexpression of a candidate gene, PRSS8, which encodes prostasin, was confirmed against 18 major human cancer types from 390 cancer samples by qRT-PCR. PRSS8 expression profiles stratified by OVC tumor stage-, grade- and subtype were generated using cDNA samples from 159 OVC samples. Cell-specific expression and localization of prostasin was determined by immunohistological tissue array analysis of more than 500 normal, benign, and cancerous ovarian tissues. The presence of prostasin in normal, benign, and OVC serum samples was also determined.ResultsGene expression analysis indicated that PRSS8 was expressed in OVC at levels more than 100 fold greater than found in normal or benign ovarian lesions. This overexpression signature was found in early stages of OVC and was maintained in higher stages and grades of OVC. The PRSS8 overexpression signature was specific for OVC and urinary bladder cancer among 18 human cancer types. The majority of ovarian cell lines overexpressed PRSS8. In situ hybridization and histopathology studies of OVC tissues indicated that overexpression of prostasin was largely localized to tumor epithelium and was absent in neighboring stroma. Significantly higher levels of prostasin were found in early stage OVC serum samples compared to benign ovarian and normal donor samples.ConclusionsThe abundant amounts of secreted prostasin found in sera of early stage OVC can potentially be used as a minimally invasive screening biomarker for early stage OVC. Overexpression of PRSS8 mRNA and high levels of prostasin in multiple subtypes of early stage ovarian tumors may provide clinical biomarkers for early detection of OVC, which can potentially be used with CA125 and HE4.Electronic supplementary materialThe online version of this article (doi:10.1186/s13048-016-0228-9) contains supplementary material, which is available to authorized users.
Highlights
Ovarian cancer (OVC) is the deadliest of all gynecologic cancers, primarily as a consequence of asymptomatic progression
Identification of PRSS8 as a potential biomarker for OVC Multiple “-omics” studies in the past two decades have produced more than 5000 publications related to biomarkers for OVC [28]
In an analysis of nearly 500 ovarian tumors and normal ovarian tissues by In situ hybridization and Immunohistochemical staining in Tissue Array format, we found that the PRSS8 gene and PRSS8 protein were both significantly upregulated in the majority of ovarian tumors (Fig. 1c)
Summary
Ovarian cancer (OVC) is the deadliest of all gynecologic cancers, primarily as a consequence of asymptomatic progression. In 2011, the FDA approved the use of blood tests for HE4 and CA125 with the Risk of Ovarian Malignancy Algorithm (ROMA), which demonstrated higher accuracy in determining risk in pre- and postmenopausal women Additional tests such as OVACheck, which is based on proteomic technology, and OvaSure, which includes CA125 among five other biomarkers, require further validation [7]. These tests demonstrate that a combination of multiple markers can generate synergistic advantages over a single marker in a clinical setting, they are primarily based on upregulation of CA125, which does not always occur These tests are mostly used for further evaluation of women who have already been diagnosed with pelvic mass and are due for surgery, rather than for initial diagnosis. There are no current FDA-cleared biomarkers for OVC screening; markers are cleared only for the limited application of monitoring disease recurrence and therapeutic response
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