Abstract
Preoperative diagnostics of ovarian neoplasms rely on ultrasound imaging and the serum biomarkers CA125 and HE4. However, these markers may be elevated in non-neoplastic conditions and may fail to identify most non-serous epithelial cancer subtypes. The objective of this study was to identify histotype-specific serum biomarkers for mucinous ovarian cancer. The candidate genes with mucinous histotype specific expression profile were identified from publicly available gene-expression databases and further in silico data mining was performed utilizing the MediSapiens database. Candidate biomarker validation was done using qRT-PCR, western blotting and immunohistochemical staining of tumor tissue microarrays. The expression level of the candidate gene in serum was compared to the serum CA125 and HE4 levels in a patient cohort of prospectively collected advanced ovarian cancer. Database searches identified REG4 as a potential biomarker with specificity for the mucinous ovarian cancer subtype. The specific expression within epithelial ovarian tumors was further confirmed by mRNA analysis. Immunohistochemical staining of ovarian tumor tissue arrays showed distinctive cytoplasmic expression pattern only in mucinous carcinomas and suggested differential expression between benign and malignant mucinous neoplasms. Finally, an ELISA based serum biomarker assay demonstrated increased expression only in patients with mucinous ovarian cancer. This study identifies REG4 as a potential serum biomarker for histotype-specific detection of mucinous ovarian cancer and suggests serum REG4 measurement as a non-invasive diagnostic tool for postoperative follow-up of patients with mucinous ovarian cancer.
Highlights
Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer [1]
REG4 is a member of the regenerating gene (REG) family, which belongs to the calciumdependent lectin superfamily
The specific mucinous lineage expression of REG4 within ovarian neoplasms was demonstrated by several ways
Summary
New treatment modalities have prolonged survival during recent decades, the overall prognosis has not improved [2,3] The symptoms, such as abdominal pain, increased abdominal size, bloating or nausea, are often non-specific until late in disease progression, leading to delayed diagnosis. The novel serum biomarker Human epididymis 4 (HE4) may bring additional information in differential diagnostics of women with pelvic mass [4]. These biomarkers, are not completely reliable for diagnosing nonserous histotypes. Mucinous ovarian tumors have been shown to have lower response rate to platinum-based chemotherapy when compared to HGSC [5,6]. Non-invasive diagnostic methods, such as histotype differentiating serum tests, could be valuable for optimization of treatment strategy before surgery
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