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Diagnostic Markers of Ovarian Cancer by High-Throughput Antigen Cloning and Detection on Arrays

¹ Program in Molecular Biology and Human Genetics, and ² Integrated Biostatistics Core, Barbara Ann Karmanos Cancer Institute and Wayne State University; Departments of ³ Pathology and ⁴ Computer Science, Wayne State University; ⁵ Division of Gynecologic Oncology and ⁶ Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan; ⁷ Department of Gynecologic Oncology, M. D. Anderson Cancer Center, Houston, Texas; ⁸ Division of Immunology and Infectious Diseases, Department of Obstetrics and Gynecology, Weill Medical College of Cornell University; and ⁹ Department of Obstetrics and Gynecologic Oncology, New York University School of Medicine, New York, New York

Requests for reprints: Michael A. Tainsky, Program in Molecular Biology and Human Genetics, Barbara Ann Karmanos Cancer Institute, 110 East Warren, Prentis 311, Detroit, MI 48201-3917. Phone: 313-833-0715, ext. 2641; Fax: 313-832-7294; E-mail: tainskym{at}karmanos.org.

A noninvasive screening test would significantly facilitate early detection of epithelial ovarian cancer. This study used a combination of high-throughput selection and array-based serologic detection of many antigens indicative of the presence of cancer, thereby using the immune system as a biosensor. This high-throughput selection involved biopanning of an ovarian cancer phage display library using serum immunoglobulins from an ovarian cancer patient as bait. Protein macroarrays containing 480 of these selected antigen clones revealed 65 clones that interacted with immunoglobulins in sera from 32 ovarian cancer patients but not with sera from 25 healthy women or 14 patients having other benign or malignant gynecologic diseases. Sequence analysis data of these 65 clones revealed 62 different antigens. Among the markers, we identified some known antigens, including RCAS1, signal recognition protein-19, AHNAK-related sequence, nuclear autoantogenic sperm protein, Nijmegen breakage syndrome 1 (Nibrin), ribosomal protein L4, Homo sapiens KIAA0419 gene product, eukaryotic initiation factor 5A, and casein kinase II, as well as many previously uncharacterized antigenic gene products. Using these 65 antigens on protein microarrays, we trained neural networks on two-color fluorescent detection of serum IgG binding and found an average sensitivity and specificity of 55% and 98%, respectively. In addition, the top 6 of the most specific clones resulted in an average sensitivity and specificity of 32% and 94%, respectively. This global approach to antigenic profiling, epitomics, has applications to cancer and autoimmune diseases for diagnostic and therapeutic studies. Further work with larger panels of antigens should provide a comprehensive set of markers with sufficient sensitivity and specificity suitable for clinical testing in high-risk populations. (Cancer Res 2006; 66(2): 1181-90)

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