Secretome-Based Identification of TFPI2, A Novel Serum\nBiomarker for Detection of Ovarian Clear Cell Adenocarcinoma

Of\nall of the epithelial ovarian cancers (EOC), clear cell adenocarcinoma\n(CCA) has the worst clinical prognosis. Furthermore, the conventional\nEOC biomarker CA125 is more often negative in CCA than in other subtypes\nof EOC. This study sought to discover a new diagnostic biomarker that\nwould allow more reliable detection of CCA. Using mass spectrometry,\nwe compared proteins in conditioned media from cell lines derived\nfrom CCA and other types of EOC. We identified 30 extracellular or\nreleased proteins specifically present in CCA-derived cell lines.\nBioinformatics analyses identified a serine protease inhibitor, tissue\nfactor pathway inhibitor 2 (TFPI2), as a potential biomarker for CCA.\nReal time RT-PCR and Western blot analyses revealed that TFPI2 was\nexclusively expressed in CCA-derived cell lines and tissues. For clinical\nvalidation, we measured levels of TFPI2 and CA125 in a set of sera\nfrom 30 healthy women, 30 patients with endometriosis, and 50 patients\nwith CCA, using an automated enzyme-linked immunosorbent assay systems.\nSerum levels of TFPI2 were significantly elevated in CCA patients,\neven those with normal CA125 levels. In terms of area under the receiver\noperating characteristic curve (AUC), TFPI2 was superior to CA125\nin discriminating CCA patients from healthy women (AUC 0.97 for TFPI2\nversus AUC 0.80 for CA125), or from patients with endometriosis (AUC\n0.93 for TFPI2 versus 0.80 for CA125). This is the first evidence\nfor TFPI2 as a serum biomarker of CCA. We propose that this biomarker\nmay be useful for detection of CCA and for monitoring the transformation\nfrom endometriosis into CCA.