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Discovery and Validation of Protein Abundance Differences between Follicular Thyroid Neoplasms

Departments of ¹ Endocrinology and ² Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands and ³ Section of Pulmonary Medicine, Department of Pediatrics, ⁴ Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, ⁵ Department of Pathology, and ⁶ University of Colorado Cancer Center, School of Medicine at the University of Colorado at Denver and Health Sciences Center, Aurora, Colorado

Requests for reprints: Bryan R. Haugen, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Colorado Cancer Center, University of Colorado at Denver and Health Sciences Center, MS 8106, P. O. Box 6511, Aurora, CO 80045. Phone: 303-724-3921; Fax: 303-724-3920. E-mail: bryan.haugen{at}uchsc.edu.

Key Words: follicular thyroid carcinoma • adenoma • proteomics • DIGE

Distinguishing between benign follicular thyroid adenoma (FTA) and malignant follicular thyroid carcinoma (FTC) by cytologic features alone is not possible. Molecular markers may aid distinguishing FTA from FTC in patients with indeterminate cytology. The aim of this study is to define protein abundance differences between FTC from FTA through a discovery (proteomics) and validation (immunohistochemistry) approach. Difference gel electrophoresis (DIGE) and peptide mass fingerprinting were performed on protein extracts from five patients with FTC and compared with six patients with FTA. Individual gel comparisons (i.e., each FTC extract versus FTA pool) were also performed for the five FTC patients. Immunohistochemical validation studies were performed on three of the identified proteins. Based on DIGE images, 680 protein spots were matched on individual gels. Of these, 102 spots showed statistically significant differences in abundance between FTC and FTA in the individual gel analyses and were therefore studied further. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used to identify 54 of these protein spots. Three candidates involved in protein folding (heat shock protein gp96, protein disulfide isomerase A3, and calreticulin) were studied by immunohistochemistry. Moderate calreticulin immunohistochemical staining was the best single marker with a high negative predictive value (88%); combining all three markers (any marker less than moderate staining) had the best positive predictive value (75%) while still retaining a good negative predictive value (68%). With DIGE, we identified 54 proteins differentially abundant between FTC and FTA. Three of these were validated by immunohistochemistry. These findings provide further insights into the diagnosis, prognosis, and pathophysiology of follicular-derived thyroid neoplasms. [Cancer Res 2008;68(5):1572–80]

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