Abstract
Abstract Background: Epithelial ovarian cancer (EOC) is a leading cause of death from gynecological malignancies in the US. The high mortality rate associated with EOC is largely due to the late disease stage at which the majority of women present clinical symptoms. CA125 (MUC16) is a serum marker used for detection of ovarian cancer. Serum CA125 is elevated in the majority of women with ovarian cancer, but its clinical usefulness is limited in part by low sensitivity for detection of early stage disease. Therefore, biomarkers that specify early stage ovarian cancer are needed. Objective: To identify markers that improve upon the performance of CA125, we searched for genes that were increased in tumors expressing only low levels of CA125 mRNA. We reasoned that such biomarkers may have utility in detecting the early stage ovarian cancers that are missed by screening for serum CA125 alone. Methods: The expression levels of CA125 and additional candidate biomarkers were measured using real-time quantitative RT-PCR across a panel of normal ovary tissue specimens and epithelial ovarian tumors. Biomarker protein levels in normal ovary and ovarian tumor tissue extracts were assessed by immunoblotting. Results: CA125 mRNA levels were characterized across a panel of 27 normal ovary specimens and 96 epithelial ovarian tumors. In 78% of the ovarian tumor tissues, levels of CA125 transcript were elevated greater than 10-fold relative to the average expression measured in the normal ovary specimens. In the remaining 21 EOC specimens, CA125 mRNA levels were much more modestly elevated, with increased expression measuring less than 10-fold relative to the normal ovarian tissues. Claudin-3 (CLDN3) was identified as a biomarker whose transcript level was elevated greater than ten-fold in 90% of EOC tissues including the subset of ovarian tumors expressing only modestly elevated levels of CA125 mRNA. In 17 of the 21 tumor specimens exhibiting only modestly elevated CA125 message (81%), CLDN3 transcript was up-regulated greater than 10-fold. CLDN3 message was up-regulated over 100-fold in 11 of these 21 specimens (52%). Eleven of the 21 tumors with low CA125 mRNA and high CLDN3 mRNA were diagnosed at an early stage (stage 1 + 2). This increased expression of CLDN3 mRNA in ovarian tumor tissues displaying only slightly elevated CA125 transcript was confirmed by immunoblotting tumor tissue lysates with a monoclonal antibody specific for CLDN3. Conclusion: The elevated expression of CLDN3 mRNA and protein in epithelial ovarian cancer tissues exhibiting only modest up-regulation of CA125 suggests that CLDN3 may complement CA125 as a biomarker for detection and management of ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2739.
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