Low molecular weight proteomic information distinguishes metastatic from benign pheochromocytoma

    1. F M Brouwers1,
    2. E F Petricoin III2,
    3. L Ksinantova3,
    4. J Breza4,
    5. V Rajapakse5,
    6. S Ross5,
    7. D Johann5,
    8. M Mannelli6,
    9. B L Shulkin7,
    10. R Kvetnansky3,
    11. G Eisenhofer8,
    12. M M Walther9,
    13. B A Hitt10,
    14. T P Conrads11,
    15. T D Veenstra11,
    16. D P Mannion12,
    17. M R Wall12,
    18. G M Wolfe12,
    19. V A Fusaro5,
    20. L A Liotta5 and
    21. K Pacak1
    1. 1Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, Bethesda, Maryland, USA
    2. 2NCI/FDA Clinical Proteomics Program, Office of Cell and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA
    3. 3Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovak Republic
    4. 4Department of Urology, Komensky Faculty of Medicine, Bratislava, Slovak Republic
    5. 5NCI/FDA Clinical Proteomics Program, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
    6. 6Department of Clinical Physiopathology, Endocrine Unit, University of Florence, Florence, Italy
    7. 7Department of Radiological Sciences, St Jude Children’s Research Hospital, Memphis, Tennessee, USA
    8. 8Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA
    9. 9Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
    10. 10Correlogic Systems Inc., Bethesda, Maryland, USA
    11. 11National Cancer Institute Biomedical Proteomics Program, Analytical Chemistry Laboratory, Mass Spectrometry Center, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland, USA
    12. 12Predictive Diagnostics Inc., Vacaville, California, USA
    1. (Requests for offprints should be addressed to K Pacak, Unit on Clinical Neuroendocrinology, RBMB, NIH, NICHD, Building 10, CRC, Room 1E-1-3140, 10 Center Drive, MSC-1109, Bethesda, Maryland 20892-1109, USA; Email: karel{at}mail.nih.gov)


    Metastatic lesions occur in up to 36% of patients with pheochromocytoma. Currently there is no way to reliably detect or predict which patients are at risk for metastatic pheochromocytoma. Thus, the discovery of biomarkers that could distinguish patients with benign disease from those with metastatic disease would be of great clinical value. Using surface-enhanced laser desorption ionization protein chips combined with high-resolution mass spectrometry, we tested the hypothesis that pheochromocytoma pathologic states can be reflected as biomarker information within the low molecular weight (LMW) region of the serum proteome. LMW protein profiles were generated from the serum of 67 pheochromocytoma patients from four institutions and analyzed by two different bioinformatics approaches employing pattern recognition algorithms to determine if the LMW component of the circulatory proteome contains potentially useful discriminatory information. Both approaches were able to identify combinations of LMW molecules which could distinguish all metastatic from all benign pheochromocytomas in a separate blinded validation set.

    In conclusion, for this study set low molecular mass biomarker information correlated with pheochromocytoma pathologic state using blinded validation. If confirmed in larger validation studies, efforts to identify the underlying diagnostic molecules by sequencing would be warranted. In the future, measurement of these biomarkers could be potentially used to improve the ability to identify patients with metastatic disease.

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