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Discovering Clinical Biomarkers of Ionizing Radiation Exposure with Serum Proteomic Analysis

¹ Radiation Oncology Branch, National Cancer Institute; ² National Cancer Institute-Food and Drug Administration Clinical Proteomics Program, Laboratory of Pathology; ³ Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH-Department of Health and Human Services; ⁴ National Cancer Institute-Food and Drug Administration Clinical Proteomics Program, Office of Cellular and Gene Therapy, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland; ⁵ Radiation Medicine Program, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada; ⁶ Department of Radiation Oncology, McGill University, Montreal, Quebec, Canada; and ⁷ Science Applications International Corporation-Frederick, Inc., Clinical Proteomics Reference Laboratory, National Cancer Institute Frederick, Gaithersburg, Maryland

Requests for reprints: Kevin Camphausen, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH-Department of Health and Human Services, Room B3B69, Building 10, 9000 Rockville Pike, Bethesda, MD 20892. Phone: 301-496-5457; Fax: 301-480-5439; E-mail: camphauk{at}mail.nih.gov.

In this study, we sought to explore the merit of proteomic profiling strategies in patients with cancer before and during radiotherapy in an effort to discover clinical biomarkers of radiation exposure. Patients with a diagnosis of cancer provided informed consent for enrollment on a study permitting the collection of serum immediately before and during a course of radiation therapy. High-resolution surface-enhanced laser desorption and ionization-time of flight (SELDI-TOF) mass spectrometry (MS) was used to generate high-throughput proteomic profiles of unfractionated serum samples using an immobilized metal ion-affinity chromatography nickel-affinity chip surface. Resultant proteomic profiles were analyzed for unique biomarker signatures using supervised classification techniques. MS-based protein identification was then done on pooled sera in an effort to begin to identify specific protein fragments that are altered with radiation exposure. Sixty-eight patients with a wide range of diagnoses and radiation treatment plans provided serum samples both before and during ionizing radiation exposure. Computer-based analyses of the SELDI protein spectra could distinguish unexposed from radiation-exposed patient samples with 91% to 100% sensitivity and 97% to 100% specificity using various classifier models. The method also showed an ability to distinguish high from low dose-volume levels of exposure with a sensitivity of 83% to 100% and specificity of 91% to 100%. Using direct identity techniques of albumin-bound peptides, known to underpin the SELDI-TOF fingerprints, 23 protein fragments/peptides were uniquely detected in the radiation exposure group, including an interleukin-6 precursor protein. The composition of proteins in serum seems to change with ionizing radiation exposure. Proteomic analysis for the discovery of clinical biomarkers of radiation exposure warrants further study. (Cancer Res 2006; 66(3): 1844-50)

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