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Whole Genome Oligonucleotide-Based Array Comparative Genomic Hybridization Analysis Identified Fibroblast Growth Factor 1 As a Prognostic Marker for Advanced-Stage Serous Ovarian Adenocarcinomas

Michael J. Birrer, Michael E. Johnson, Ke Hao, Kwong-Kwok Wong, Dong-Choon Park, Aaron Bell, William R. Welch, Ross S. Berkowitz, Samuel C. Mok

From the Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; Department of Obstetrics and Gynecology, Gynecologic Oncology; and the Department of Pathology, Brigham and Women's Hospital, Harvard Medical School; Department of Biostatistics, Harvard School of Public Health; Gillette Center for Women's Cancer, Dana-Farber Harvard Cancer Center, Boston, MA; Department of Gynecologic Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX; and the Department of Obstetrics and Gynecology, Saint Vincent Hospital, The Catholic University of Korea, Suwon, Korea

Address reprint requests to Samuel C. Mok, PhD, Laboratory of Gynecologic Oncology Brigham and Women's Hospital, BLI-447, 221 Longwood Ave, Boston, MA 02115; e-mail: scmok{at}rics.bwh.harvard.edu

Purpose: To identify markers that can predict overall survival in patients with high-grade advanced stage serous adenocarcinomas.

Patients and Methods: Oligonucleotide array comparative genomic hybridization (aCGH) was performed on 42 microdissected high-grade serous ovarian tumor samples. aCGH segments were obtained and a prediction Cox model was built and validated by the standard leave one out analysis. Both DNA and mRNA copy numbers of selected genes located on the candidate aCGH segments were determined by quantitative polymerase chain reaction (qPCR) and quantitative reverse transcriptase PCR (qRT-PCR) analyses. The gene that showed the highest correlation was further validated on an independent set of specimens and was selected for further functional studies.

Results: Two chromosomal regions, 4p16.3 and 5q31-5q35.3, exhibited the strongest correlation with overall survival (P < .01). From the 5q31 region, fibroblast growth factor 1 (FGF-1) was selected for further validation study. FGF-1 mRNA copy number was significantly correlated with DNA copy number and protein expression levels (P = .021 and < .001), and both FGF-1 mRNA and protein levels were significantly associated with overall survival (P = .018 and .042). This association was validated for protein expression on an independent set of 81 samples, significant to P = .006. Further studies showed significant correlation between FGF-1 protein expression and CD31+ staining in the tumor stroma (P = .024). Finally, both cancer cells and endothelial cells treated with exogenous FGF-1 showed a significant increase in cell motility and survival.

Conclusion: Amplification of FGF-1 at 5q31 in ovarian cancer tissues leads to increased angiogenesis, and autocrine stimulation of cancer cells, which may result in poorer overall survival in patents with high-grade advanced stage serous ovarian cancer.

Supported in part by Dana-Farber/Harvard Cancer Center Ovarian Cancer SPORE Grants No. P50CA105009, R33CA103595, and M.D. Anderson Ovarian SPORE Grant No. P50CA083639 from National Institutes of Health, Department of Health and Human Services, Gillette Center for Women's Cancer, Adler Foundation Inc, Edgar Astrove Fund, the Ovarian Cancer Research Fund Inc, the Morse Family fund, the Natalie Pihl fund, the Ruth N. White research fellowship, Friends of Dana Farber Cancer Institute, the Robert and Deborah First fund, and the intramural research program of the National Cancer Institute.

Presented in part at the 97th Annual Meeting of the American Association for Cancer Research, April 1-5, 2006, Washington, DC.

M.J.B. and M.E.J. contributed equally to this study.

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