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BRAF Mutations in Thyroid Tumors Are Restricted to Papillary Carcinomas and Anaplastic or Poorly Differentiated Carcinomas Arising from Papillary Carcinomas

Department of Pathology and Laboratory Medicine (M.N.N., M.G., P.W.B., Z.Z., Y.E.N.) and Division of Endocrinology (E.T.K., J.A.K., J.A.F.), University of Cincinnati, Cincinnati, Ohio; Dipartimento di Oncologia (F.B., R.G.), Pisa, Italy; and Dipartimento di Biologia e Patologia Cellulare e Molecolare (G.S., A.F., M.S.), University ‘Federico II’ c/o Istituto di Endocrinologia ed Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Naples, Italy

Address all correspondence and requests for reprints to: Dr. Yuri Nikiforov, Department of Pathology, University of Cincinnati, 231 Albert Sabin Way, P.O. Box 670529, Cincinnati, Ohio 45267-0529. E-mail: yuri.nikiforov{at}uc.edu.

Activating point mutations of the BRAF gene have been recently reported in papillary thyroid carcinomas. In this study, we analyzed 320 thyroid tumors and six anaplastic carcinoma cell lines and detected BRAF mutations in 45 (38%) papillary carcinomas, two (13%) poorly-differentiated carcinomas, three (10%) anaplastic carcinomas, and five (83%) thyroid anaplastic carcinoma cell lines but not in follicular, Hürthle cell, and medullary carcinomas, follicular and Hürthle cell adenomas, or benign hyperplastic nodules. All mutations involved a TA transversion at nucleotide 1796. In papillary carcinomas, BRAF mutations were associated with older age, classic papillary carcinoma or tall cell variant histology, extrathyroidal extension, and more frequent presentation at stages III and IV. All BRAF-positive poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and mutation was present in both the well-differentiated and dedifferentiated components. These data indicate that BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas. They are associated with distinct phenotypical and biological properties of papillary carcinomas and may participate in progression to poorly differentiated and anaplastic carcinomas.

This work was supported by the American Cancer Society Grant RSG-03-027-01-CCE (to Y.E.N.), National Institutes of Health (NIH) Grant CA50706 (to J.A.F.), and funds from the Italian Association for Cancer Research. Tissue samples were collected, in part, using a support by grant from the NIH (PHS M01 RR08084 to the Children’s Hospital-University of Cincinnati General Clinical Research Center Tissue Procurement Facility) and through the Cooperative Human Tissue Network, which is funded by the National Cancer Institute.

Abbreviations: FMCA, Fluorescence melting curve analysis; SSCP, single-strand conformational polymorphism; V599E, valine-to-glutamate substitution at residue 599; WT, wild-type.

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				G. Salvatore, R. Giannini, P. Faviana, A. Caleo, I. Migliaccio, J. A. Fagin, Y. E. Nikiforov, G. Troncone, L. Palombini, F. Basolo, et al. Analysis of BRAF Point Mutation and RET/PTC Rearrangement Refines the Fine-Needle Aspiration Diagnosis of Papillary Thyroid Carcinoma J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 5175 - 5180. [Abstract] [Full Text] [PDF]

				J. A. Fagin Challenging Dogma in Thyroid Cancer Molecular Genetics--Role of RET/PTC and BRAF in Tumor Initiation J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4264 - 4266. [Full Text] [PDF]

				J. Lima, V. Trovisco, P. Soares, V. Maximo, J. Magalhaes, G. Salvatore, M. Santoro, T. Bogdanova, M. Tronko, A. Abrosimov, et al. BRAF Mutations Are Not a Major Event in Post-Chernobyl Childhood Thyroid Carcinomas J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4267 - 4271. [Abstract] [Full Text] [PDF]

				A. Kumagai, H. Namba, V. A. Saenko, K. Ashizawa, A. Ohtsuru, M. Ito, N. Ishikawa, K. Sugino, K. Ito, S. Jeremiah, et al. Low Frequency of BRAFT1796A Mutations in Childhood Thyroid Carcinomas J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4280 - 4284. [Abstract] [Full Text] [PDF]

				M. Xing, R. P. Tufano, A. P. Tufaro, S. Basaria, M. Ewertz, E. Rosenbaum, P. J. Byrne, J. Wang, D. Sidransky, and P. W. Ladenson Detection of BRAF Mutation on Fine Needle Aspiration Biopsy Specimens: A New Diagnostic Tool for Papillary Thyroid Cancer J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2867 - 2872. [Abstract] [Full Text] [PDF]

				E. Puxeddu, S. Moretti, R. Elisei, C. Romei, R. Pascucci, M. Martinelli, C. Marino, N. Avenia, E. D. Rossi, G. Fadda, et al. BRAFV599E Mutation Is the Leading Genetic Event in Adult Sporadic Papillary Thyroid Carcinomas J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2414 - 2420. [Abstract] [Full Text] [PDF]

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