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Verification of Endometrial Tissue Biomarkers Previously Discovered Using Mass Spectrometry-Based Proteomics by Means of Immunohistochemistry in a Tissue Microarray Format

Valerie Dubé,^† Jörg Grigull,^‡ Leroi V. DeSouza,^§ Shaun Ghanny,^§ Terence J. Colgan,*^† Alexander D. Romaschin, and K. W. Michael Siu^§

Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5, Department of Mathematics and Statistics, York University, 4700 Keele Street, Toronto, Ontario, Canada M2J 1P3, Departments of Chemistry and Biology, and Centre of Research in Mass Spectrometry, York University, Toronto, Ontario, Canada M2J 1P3, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M5G 1X5, and Division of Clinical Biochemistry, St. Michael's Hospital, 30 Bond Street, Toronto, Ontario, Canada M5B 1W8

J. Proteome Res., 2007, 6 (7), pp 2648–2655

DOI: 10.1021/pr070087o

Publication Date (Web): June 7, 2007

†

Pathology and Laboratory Medicine, Mount Sinai Hospital.

‡

Department of Mathematics and Statistics, York University.

Departments of Chemistry and Biology, and Centre of Research in Mass Spectrometry, York University.

Corresponding author: Dr. Terence J. Colgan, Room 6-502-3, Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada M5G 1X5. Tel, (416) 586-4522; fax, (416) 586-8481; e-mail, tcolgan@mtsinai.on.ca.

Department of Laboratory Medicine and Pathobiology, University of Toronto.

Division of Clinical Biochemistry, St. Michael's Hospital.

Abstract

Verification of candidate protein biomarkers is a necessary step in moving from the initial discovery to application. Here, we report results of a verification exercise involving six candidate endometrial cancer biomarkers previously discovered using mass-tagging and multidimensional liquid chromatography/tandem mass spectrometry (DeSouza L., et al. J. Proteome Res. 2005, 4, 377−386) on a cohort of 148 patient samples by means of immunohistochemistry on a tissue microarray format. A panel of the three best-performing biomarkers, chaperonin 10, pyruvate kinase M2, and α-1-antitrypsin, achieved a sensitivity of 0.85, specificity of 0.93, predictive value of 0.90, and positive predictive value of 0.88 in discriminating malignant from benign endometrium. The ruggedness of this panel of biomarkers was verified in a 2/3-training-set−1/3-test-set cross-validation analysis by randomly splitting the cohort in 10 ways. The roles of chaperonin 10 and pyruvate kinase M2 in tumorigenesis confirm them as credible cancer biomarkers.

Keywords: Verification • Biomarkers • Endometrial carcinoma • Tissue proteomics • Immunohistochemistry • Tissue Microarray • Chaperonin-10 • Pyruvate kinase M2

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