title: REG4 Is Highly Expressed in Mucinous Ovarian Cancer: A Potential Novel Serum Biomarker.
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.
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Lehtinen
authors.affiliation: VTT Technical Research Centre of Finland, Espoo and Turku Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Vesterkvist
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Roering
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Taina
authors.initials: T
authors.lastname: Korpela
authors.affiliation: VTT Technical Research Centre of Finland, Espoo and Turku Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Liisa
authors.initials: L
authors.lastname: Hattara
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Katja
authors.initials: K
authors.lastname: Kaipio
authors.affiliation: FIMM, Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: John-Patrick
authors.initials: JP
authors.lastname: Mpindi
authors.affiliation: Department of Obstetrics and Gynecology, Turku University Hospital, University of Turku, Turku, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Hynninen
authors.affiliation: Department of Obstetrics and Gynecology, Turku University Hospital, University of Turku, Turku, Finland.
authors.forename: Annika
authors.initials: A
authors.lastname: Auranen
authors.affiliation: Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway.|University of Oslo, Faculty of Medicine, Institute of Clinical Medicine, Oslo, Norway.
authors.forename: Ben
authors.initials: B
authors.lastname: Davidson
authors.affiliation: Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland.
authors.forename: Caj
authors.initials: C
authors.lastname: Haglund
authors.affiliation: VTT Technical Research Centre of Finland, Espoo and Turku Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Iljin
authors.affiliation: Department of Obstetrics and Gynecology, Turku University Hospital, University of Turku, Turku, Finland.
authors.forename: Seija
authors.initials: S
authors.lastname: Grenman
authors.affiliation: VTT Technical Research Centre of Finland, Espoo and Turku Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Harri
authors.initials: H
authors.lastname: Siitari
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Carpen
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism; D018394:CA-125 Antigen / Q000097:blood; D016208:Databases, Factual; D005260:Female; D006801:Humans; D037181:Lectins, C-Type / Q000097:blood / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins / Q000378:metabolism; D000081102:WAP Four-Disulfide Core Domain Protein 2
chemical_list: D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; C428528:REG4 protein, human; D000081102:WAP Four-Disulfide Core Domain Protein 2; C569698:WFDC2 protein, human