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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 9 4393-4397
Copyright © 2003 by The Endocrine Society

Clinical Implication of Hot Spot BRAF Mutation, V599E, in Papillary Thyroid Cancers

Hiroyuki Namba, Masahiro Nakashima, Tomayoshi Hayashi, Naomi Hayashida, Shigeto Maeda, Tatiana I. Rogounovitch, Akira Ohtsuru, Vladimir A. Saenko, Takashi Kanematsu and Shunichi Yamashita

Department of Molecular Medicine (H.N., T.I.R., A.O., S.Y.), Tissue and Histopathology Section; Division of Scientific Data Registry (M.N.), International Health and Radiation Research (V.A.S., S.Y.), Atomic Bomb Disease Institute; Departments of Pathology (T.H.) and Division of Endocrine Surgery (S.M.); and Department of Surgery (N.H., T.K.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8523, Japan

Address all correspondence and requests for reprints to: Prof. Hiroyuki Namba, M.D., Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan. E-mail: namba{at}net.nagasaki-u.ac.jp.

Activating mutations in the BRAF kinase gene have recently been reported in human cancers. The aim of the present study was to determine the frequency of BRAF mutations in thyroid cancer and their correlation with clinicopathological parameters. We analyzed exons 11 and 15 of BRAF gene in six human thyroid cancer cell lines and 207 paraffin-embedded thyroid tumor tissues. A missense mutation was found at T1796A (V599E) in exon 15 in four of the six cell lines and 51 of 207 thyroid tumors (24.6%; 0 of 20 follicular adenoma, 0 of 11 follicular carcinoma, 49 of 170 papillary carcinomas, and 2 of 6 undifferentiated carcinomas). Activation of MAPK kinase-MAPK pathway was observed in cell lines harboring BRAF mutation. BRAF mutation-associated enhanced cell growth was suppressed by MAPK kinase inhibitor, U0126. Examination of 126 patients with papillary thyroid cancer showed that BRAF mutation correlated significantly with distant metastasis (P = 0.033) and clinical stage (P = 0.049). Our results indicate that activating mutation of BRAF gene could be a potentially useful marker of prognosis of patients with advanced thyroid cancers.

This work was supported by Grants-in-Aid for Scientific Research 13671158, 14380256, and 12576020 from The Ministry of Education, Culture, Sports, Science and Technology.

Abbreviations: FBS, Fetal bovine serum; MEK, MAPK kinase.




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