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Use of a Combination of Approaches to Identify and Validate Relevant Tumor-Associated Antigens and Their Corresponding Autoantibodies in Ovarian Cancer Patients

Authors' Affiliations: ¹ Laboratory of Gynecologic Oncology, Division of Gynecology Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, ² Department of Urology, and ³ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School; ⁴ Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Dana-Farber Harvard Cancer Center, Harvard Medical School, Boston, Massachusetts; ⁵ Department of Obstetrics and Gynecology, Yongdong Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; ⁶ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas; and ⁷ Program in Women's Oncology, Women and Infants' Hospital, Brown University School of Medicine, Providence, Rhode Island

Requests for reprints: Samuel C. Mok, Laboratory of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115. Phone: 617-278-0196; Fax: 617-975-0818; E-mail: scmok{at}rics.bwh.harvard.edu.

Purpose: Novel biomarkers are urgently needed to increase the sensitivity of CA125 for the early detection of ovarian cancer. Indeed, it has been shown that as much as 20% of early-stage patients do not express significant levels of this biomarker. Therefore, the possibility of using autoantibodies directed against tumor-associated antigens as putative cancer markers is being more examined. Indeed, many autoantibodies have recently been shown to correlate with cancer patient prognosis or to be suitable for detection of the disease.

Experimental Design: In this study, we have used a new approach involving the use of proteomics, immunology, and ELISA methods to identify relevant autoantibodies in the plasma of ovarian cancer patients. To do so, we developed an innovative technique called two-dimensional differential gel electrophoresis analysis of immunoprecipitated tumor antigens.

Results: This strategy allowed us to successfully identify novel circulating autoantibodies directed against the S100A7 protein in the plasma of ovarian cancer patients. Further real-time reverse transcription-PCR and immunohistochemical studies confirmed that the S100A7 mRNA and protein were highly expressed in ovarian tumors but absent in normal and benign tissues. Moreover, a preliminary study involving 138 patients confirmed that the plasma levels of anti-S100A7 antibodies are significantly elevated in early- and late-stage ovarian cancer patients compared with healthy controls and with patients with benign gynecologic diseases.

Conclusions: This shows that our approach is a valuable tool to successfully identify autoantibodies and tumor-associated antigens in cancer patients and that future research assessing their putative clinical usefulness would be worthwhile.