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ERCC5 Is a Novel Biomarker of Ovarian Cancer Prognosis

Christine S. Walsh, Seishi Ogawa, Hisae Karahashi, Daniel R. Scoles, James C. Pavelka, Hang Tran, Carl W. Miller, Norihiko Kawamata, Charles Ginther, Judy Dering, Masashi Sanada, Yasuhito Nannya, Dennis J. Slamon, H. Phillip Koeffler, Beth Y. Karlan

From the Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, and Department of Medicine, Division of Hematologic Oncology, Cedars-Sinai Women's Cancer Research Institute at the Samuel Oschin Comprehensive Cancer Institute, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA; and Department of Hematology/Oncology, Graduate School of Medicine, University of Tokyo, Hongo, Tokyo, Japan

Corresponding author: Christine Walsh, MD, MS, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Suite 160W, Los Angeles, CA 90048; e-mail: walshc{at}cshs.org

Purpose To identify a biomarker of ovarian cancer response to chemotherapy.

Patients and Methods Study participants had epithelial ovarian cancer treated with surgery followed by platinum-based chemotherapy. DNA and RNA were isolated from frozen tumors and normal DNA was isolated from matched peripheral blood. A whole-genome loss of heterozygosity (LOH) analysis was performed using a high-density oligonucleotide array. Candidate genomic areas that predicted enhanced response to chemotherapy were identified with Cox proportional hazards methods. Gene expression analyses were performed through microarray experiments. Candidate genes were tested for independent effects on survival using Cox proportional hazards models, Kaplan-Meier survival curves, and the log-rank test.

Results Using a whole-genome approach to study the molecular determinants of ovarian cancer response to platinum-based chemotherapy, we identified LOH of a 13q region to predict prolonged progression-free survival (PFS; hazard ratio, 0.23; P = .006). ERCC5 was identified as a candidate gene in this region because of its known function in the nucleotide excision repair pathway, the unique DNA repair pathway that removes platinum-DNA adducts. We found LOH of the ERCC5 gene locus and downregulation of ERCC5 gene expression to predict prolonged PFS. Integration of genomic and gene expression data shows a correlation between 13q LOH and ERCC5 gene downregulation.

Conclusion ERCC5 is a novel biomarker of ovarian cancer prognosis and a potential therapeutic target of ovarian cancer response to platinum chemotherapy.

Supported by Borden Family Foundation (D.R.S., H.K.), Milken Family Foundation (C.S.W., B.Y.K.), Pacific Ovarian Cancer Foundation (Grant No. P50 CA83636; Principal Investigator, Nicole Urban; Carerr Development Grant to C.S.W.), General Clinical Research Center Grant No. M01-RR00425 (C.S.W.), Revlon/University of California at Los Angeles Women's Cancer Research Program (D.J.S.), Entertainment Industries Foundation (D.J.S.), and Grant-in-Aid for Scientific Research supported by the Japan Society for the Promotion of Science (S.O.).

Presented in part at the 11th Biennial Meeting of the International Gynecologic Cancer Society, October 14-18, 2006, Santa Monica, CA, and the 38th Annual Meeting of the Society of Gynecologic Oncologists, March 3-7, 2007, San Diego, CA.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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