Originally published as JCO Early Release 10.1200/JCO.2007.12.1053 on December 3 2007

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Protein Biomarker Identification in the CSF of Patients With CNS Lymphoma

Sushmita Roy, S. Andrew Josephson, Jane Fridlyand, Jon Karch, Cigall Kadoch, Juliana Karrim, Lloyd Damon, Patrick Treseler, Sandeep Kunwar, Marc A. Shuman, Ted Jones, Christopher H. Becker, Howard Schulman, James L. Rubenstein

From PPD Biomarker Discovery Sciences, LLC, Menlo Park, CA; Departments of Neurology, Epidemiology and Biostatistics, Pathology, and Neurological Surgery; and the Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA

Corresponding author: James L. Rubenstein, MD, PhD, Division of Hematology/Oncology, University of California, San Francisco, 505 Parnassus Ave, Suite M1282, San Francisco, CA 94143-1270; e-mail: jamesr{at}medicine.ucsf.edu

Purpose: Elucidation of the CSF proteome may yield insights into the pathogenesis of CNS disease. We tested the hypothesis that individual CSF proteins distinguish CNS lymphoma from benign focal brain lesions.

Methods: We used a liquid chromatography/mass spectrometry–based method to differentially quantify and identify several hundred CSF proteins in CNS lymphoma and control patients. We used enzyme-linked immunosorbent assay (ELISA) to confirm one of these markers in an additional validation set of 101 cases.

Results: Approximately 80 CSF proteins were identified and found to be present at significantly different concentrations, both higher and lower, in training and test studies, which were highly concordant. To further validate these observations, we defined in detail the expression of one of these candidate biomarkers, antithrombin III (ATIII). ATIII RNA transcripts were identified within CNS lymphomas, and ATIII protein was localized selectively to tumor neovasculature. Determination of ATIII concentration by ELISA was significantly more accurate (> 75% sensitivity; > 98% specificity) than cytology in the identification of cancer. Measurement of CSF ATIII levels was found to potentially enhance the ability to diagnose and predict outcome.

Conclusion: Our findings demonstrate for the first time that proteomic analysis of CSF yields individual biomarkers with greater sensitivity in the identification of cancer than does CSF cytology. We propose that the discovery of CSF protein biomarkers will facilitate early and noninvasive diagnosis in patients with lesions not amenable to brain biopsy, as well as provide improved surrogates of prognosis and treatment response in CNS lymphoma and brain metastasis.

published online ahead of print at www.jco.org on December 3, 2007.

Supported by the National Institutes of Health Brain Tumor SPORE (Grant No. P50 CA097267), a National Cancer Institute Research Career Award, and by grants from the American Cancer Society, the American Society of Clinical Oncology, a UC Discovery grant, the Canary Foundation, and the California Tobacco-Related Disease Research Program.

Presented at the 48th Annual Meeting of the American Society of Hematology, December 9-12, 2006, Orlando, FL.

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