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Jae-Hoon Kim, MD; Steven J. Skates, PhD; Toshimitsu Uede, MD; Kwong-kwok Wong, PhD; John O. Schorge, MD; Colleen M. Feltmate, MD; Ross S. Berkowitz, MD; Daniel W. Cramer, MD,ScD; Samuel C. Mok, PhD

JAMA. 2002;287:1671-1679.

Context  Development of new biomarkers for ovarian cancer is needed for early detection and disease monitoring. Analyses involving complementary DNA (cDNA) microarray data can be used to identify up-regulated genes in cancer cells, whose products may then be further validated as potential biomarkers.

Objective  To describe validation studies of an up-regulated gene known as osteopontin, previously identified using a cDNA microarray system.

Design, Setting, and Participants  Experimental and cross-sectional studies were conducted involving ovarian cancer and healthy human ovarian surface epithelial cell lines and cultures, archival paraffin-embedded ovarian tissue collected between June 1992 and June 2001, and fresh tissue and preoperative plasma from 144 patients evaluated for a pelvic mass between June 1992 and June 2001 in gynecologic oncology services at 2 US academic institutions. Plasma samples from 107 women selected from an epidemiologic study of ovarian cancer initiated between May 1992 and March 1997 were used as healthy controls.

Main Outcome Measures  Relative messenger RNA expression in cancer cells and fresh ovarian tissue, measured by real-time polymerase chain reaction as 2^-CT(a quantitative value representing the amount of osteopontin expression); osteopontin production, localized and scored in ovarian healthy and tumor tissue with immunohistochemical studies; and amount of osteopontin in patient vs control plasma, measured using an enzyme-linked immunoassay.

Results  The geometric mean for 2^-CTfor osteopontin expression in 5 healthy ovarian epithelial cell cultures was 4.1 compared with 270.4 in 14 ovarian cancer cell lines (P = .03). The geometric mean 2^-CTfor osteopontin expression in tissue from 2 healthy ovarian epithelial samples was 9.0 compared with 164.0 in 27 microdissected ovarian tumor tissue samples (P = .06). Immunolocalization of osteopontin showed that tissue samples from 61 patients with invasive ovarian cancer and 29 patients with borderline ovarian tumors expressed higher levels of osteopontin than tissue samples from 6 patients with benign tumors and samples of healthy ovarian epithelium from 3 patients (P = .03). Osteopontin levels in plasma were significantly higher (P<.001) in 51 patients with epithelial ovarian cancer (486.5 ng/mL) compared with those of 107 healthy controls (147.1 ng/mL), 46 patients with benign ovarian disease (254.4 ng/mL), and 47 patients with other gynecologic cancers (260.9 ng/mL).

Conclusions  Our findings provide evidence for an association between levels of a biomarker, osteopontin, and ovarian cancer and suggest that future research assessing its clinical usefulness would be worthwhile.

Author Affiliations: Department of Obstetrics and Gynecology, Saint Vincent Hospital and Catholic University of Korea, Suwon, Kyong-Ki-Do, Korea (Dr Kim); Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School (Drs Kim, Feltmate, Berkowitz, Cramer, and Mok), Massachusetts General Hospital Biostatistics Center and Harvard Medical School (Dr Skates), Dana-Farber Cancer Institute (Drs Skates, Berkowitz, and Cramer), and Dana-Farber Harvard Cancer Center (Drs Skates, Berkowitz, Cramer, and Mok), Boston, Mass; Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan (Dr Uede); Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston (Dr Wong); Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas (Dr Schorge).

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