© 2003 by Oxford University Press
Journal of the National Cancer Institute, Vol. 95, No. 8, 625-627,
April 16, 2003
© 2003 Oxford University Press
BRIEF COMMUNICATION |
BRAF Mutation in Papillary Thyroid Carcinoma
Affiliations of authors: Y. Cohen, E. Mambo, Z. Guo, G. Wu, B. Trink, W. H. Westra, D. Sidransky (Division of Head and Neck Cancer Research, Department of Otolaryngology–Head and Neck Surgery), M. Xing, P. W. Ladenson (Division of Endocrinology and Metabolism), The Johns Hopkins University School of Medicine, Baltimore, MD; U. Beller, Department of Obstetrics and Gynecology, Shaare Zedek Medical Center, Ben-Gurion University of the Negev, Jerusalem, Israel.
Correspondence to: David Sidransky, M.D., Division of Head and Neck Cancer Research, Department of Otolaryngology–Head and Neck Surgery, The Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross Bldg. 818, Baltimore, MD 21205-2196 (e-mail: dsidrans{at}jhmi.edu).
ABSTRACT
The BRAF gene has been found to be activated by mutation in human cancers, predominantly in malignant melanoma. We tested 476 primary tumors, including 214 lung, 126 head and neck, 54 thyroid, 27 bladder, 38 cervical, and 17 prostate cancers, for the BRAF T1796A mutation by polymerase chain reaction (PCR)–restriction enzyme analysis of BRAF exon 15. In 24 (69%) of the 35 papillary thyroid carcinomas examined, we found a missense thymine (T)
adenine (A) transversion at nucleotide 1796 in the BRAF gene (T1796A). The T1796A mutation was detected in four lung cancers and in six head and neck cancers but not in bladder, cervical, or prostate cancers. Our data suggest that activating BRAF mutations may be an important event in the development of papillary thyroid cancer.
The RAF proteins are highly conserved serine/threonine protein kinases that have an important role in cell proliferation, differentiation, and programmed cell death (1). The RAF proteins activate mitogen-activated protein kinase kinase (MEK), which in turn activates the mitogen-activated protein kinase (MAPK) pathway (2). Inappropriate and/or continuous activation of this pathway provides a potent promitogenic force resulting in abnormal proliferation and differentiation in many human cancers (3). Davies et al. (4) reported that BRAF is frequently mutated in a variety of human tumors, especially in malignant melanoma and colon carcinoma. The most common reported mutation was a missense thymine (T)
adenine (A) transversion at nucleotide 1796 (T1796A; amino acid change in the BRAF protein = Val599Glu599) observed in 80% of the malignant melanoma tumors. Functional analysis revealed that this transversion was the only detected mutation that caused constitutive activation of BRAF kinase activity, independent of RAS activation, by converting BRAF into a dominant transforming protein (4). In this study, we investigated the frequency of BRAF T1796A mutation and further elucidated the importance of this mutation in various primary human tumors.
We screened 476 primary tumors, including 214 lung, 126 head and neck, 54 thyroid, 27 bladder, 38 cervical, and 17 prostate cancers for the BRAF T1796A mutation by polymerase chain reaction (PCR)–restriction enzyme analysis. The samples were obtained from patients treated at The Johns Hopkins Medical Institutions (Baltimore, MD) and were collected in our tissue bank. Written informed consent was obtained from each patient in accordance with the institutional review board at The Johns Hopkins Medical Institutions. PCR amplification of exon 15 followed by digestion of the exon 15 products by the restriction endonuclease TspRI identified the BRAF T1796A mutation. TspRI digestion of the PCR fragment yielded three major bands at 125 base pairs (bp), 87 bp, and 12 bp in the wild-type allele. The T1796A mutation abolished the restriction site, resulting in a prominent 212-bp band from the mutant allele and residual bands from the normal allele (Fig. 1, A
). Reamplification of BRAF exon 15 followed by direct manual sequencing of five samples validated the results of the TspRI assay (Fig. 1, B). As positive controls for the BRAF T1796A mutation, we used melanoma cell lines HTB71, HTB72, and A2058; for negative controls, we used cell lines ME180 (cervical cancer) and HCT116 (colorectal carcinoma).
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The BRAF T1796A mutation was identified in 24 (69%) of 35 papillary thyroid carcinomas (Table 1
), six (4.8%) of 126 head and neck cancers, and four (1.9%) of 214 lung cancers. Moreover, we analyzed nine common thyroid cell lines (KAK1, KAT5, KAT7, KAT10, DRO, ARO, MRO 87–1, WRO–821, and C643) and found the same BRAF mutation in six (67%) of the nine lines. We also completely sequenced exons 11 and 15 in all T1796A-negative papillary thyroid cancers and in 10 T1796A-positive tumors but did not identify additional BRAF mutations. We did not identify any mutations in bladder, cervical, and prostate primary tumors, and no mutation was identified in biopsy samples from 20 patients with benign thyroid conditions (nodular goiter, follicular adenoma, atypical follicular adenoma, and adenomatous hyperplasia), 13 patients with follicular thyroid carcinoma, three patients with medullary thyroid carcinoma, and three patients with Hürthle cell carcinoma.
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Papillary and follicular thyroid carcinomas originate from thyroid follicular epithelial cells. To date, oncogenic mutations in RAS and RET/PTC rearrangements have been observed in follicular thyroid carcinoma and papillary thyroid carcinomas, respectively (5,6). RAS mutations are common in follicular thyroid cancers, reaching 50% in some studies, but are less common (5%–20%) in papillary thyroid tumors (5). Our observation of a high frequency of BRAF-activating mutations in papillary thyroid carcinoma suggests that BRAF activation and, in turn, activation of the RAF/MEK/MAPK signaling pathway, is a common biologic mechanism in the development of human papillary thyroid carcinoma. This observation is also consistent with the reported inverse association between the presence of BRAF and RAS mutations in other cancer types (4,7,8). The relationship between BRAF T1796A mutation and RET/PTC rearrangements remains to be explored.
The importance of the RAS pathway in thyroid cancers is further suggested by the common presence of RET mutations in medullary thyroid tumors and their transforming effect through activation of the RAS/RAF/MEK pathway (9). Moreover, activation of the RAS/RAF/MEK/MAPK pathway is known to induce genomic instability in thyroid PCCL-3 cells (10), and inhibition of the MAPK pathway has led to decreased cellular proliferation of human thyroid cancer cell lines (11). Thus, activation at various points in the RAS/RAF/MEK/MAPK pathway is a key event in the most common type of malignant thyroid tumor. The high frequency of BRAF mutations in melanoma and papillary thyroid carcinoma suggests that inhibition of BRAF activity by the newly developed RAF kinase inhibitors (12) may offer a new strategy in the treatment of these tumors. Our results have identified the BRAF T1796A mutation and likely activation of the RAF/MEK/MAPK signaling pathway as a major mechanism in the development of primary papillary thyroid carcinoma.
NOTES
M. Xing and E. Mambo contributed equally to this work.
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Manuscript received September 25, 2002; revised January 30, 2003; accepted February 6, 2003.
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M. O. Hoque, E. Rosenbaum, W. H. Westra, M. Xing, P. Ladenson, M. A. Zeiger, D. Sidransky, and C. B. Umbricht Quantitative Assessment of Promoter Methylation Profiles in Thyroid Neoplasms J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4011 - 4018. [Abstract] [Full Text] [PDF]
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 T. M. Shattuck, W. H. Westra, P. W. Ladenson, and A. Arnold Independent Clonal Origins of Distinct Tumor Foci in Multifocal Papillary Thyroid Carcinoma N. Engl. J. Med., June 9, 2005; 352(23): 2406 - 2412. [Abstract] [Full Text] [PDF]
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M Xing BRAF mutation in thyroid cancer Endocr. Relat. Cancer, June 1, 2005; 12(2): 245 - 262. [Abstract] [Full Text] [PDF]
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S Rossi, L Fugazzola, L De Pasquale, P Braidotti, V Cirello, P Beck-Peccoz, S Bosari, and A Bastagli Medullary and papillary carcinoma of the thyroid gland occurring as a collision tumour: report of three cases with molecular analysis and review of the literature Endocr. Relat. Cancer, June 1, 2005; 12(2): 281 - 289. [Abstract] [Full Text] [PDF]
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J. A. Knauf, X. Ma, E. P. Smith, L. Zhang, N. Mitsutake, X.-H. Liao, S. Refetoff, Y. E. Nikiforov, and J. A. Fagin Targeted Expression of BRAFV600E in Thyroid Cells of Transgenic Mice Results in Papillary Thyroid Cancers that Undergo Dedifferentiation Cancer Res., May 15, 2005; 65(10): 4238 - 4245. [Abstract] [Full Text] [PDF]
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V. Porra, C. Ferraro-Peyret, C. Durand, S. Selmi-Ruby, H. Giroud, N. Berger-Dutrieux, M. Decaussin, J.-L. Peix, C. Bournaud, J. Orgiazzi, et al. Silencing of the Tumor Suppressor Gene SLC5A8 Is Associated with BRAF Mutations in Classical Papillary Thyroid Carcinomas J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 3028 - 3035. [Abstract] [Full Text] [PDF]
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C. M. Caudill, Z. Zhu, R. Ciampi, J. R. Stringer, and Y. E. Nikiforov Dose-Dependent Generation of RET/PTC in Human Thyroid Cells after in Vitro Exposure to {gamma}-Radiation: A Model of Carcinogenic Chromosomal Rearrangement Induced by Ionizing Radiation J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2364 - 2369. [Abstract] [Full Text] [PDF]
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N. Mitsutake, J. A. Knauf, S. Mitsutake, C. Mesa Jr., L. Zhang, and J. A. Fagin Conditional BRAFV600E Expression Induces DNA Synthesis, Apoptosis, Dedifferentiation, and Chromosomal Instability in Thyroid PCCL3 Cells Cancer Res., March 15, 2005; 65(6): 2465 - 2473. [Abstract] [Full Text] [PDF]
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M. L. Motti, D. Califano, G. Troncone, C. De Marco, I. Migliaccio, E. Palmieri, L. Pezzullo, L. Palombini, A. Fusco, and G. Viglietto Complex Regulation of the Cyclin-Dependent Kinase Inhibitor p27kip1 in Thyroid Cancer Cells by the PI3K/AKT Pathway: Regulation of p27kip1 Expression and Localization Am. J. Pathol., March 1, 2005; 166(3): 737 - 749. [Abstract] [Full Text] [PDF]
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R. Sorrentino, S. Libertini, P. L. Pallante, G. Troncone, L. Palombini, V. Bavetsias, D. Spalletti-Cernia, P. Laccetti, S. Linardopoulos, P. Chieffi, et al. Aurora B Overexpression Associates with the Thyroid Carcinoma Undifferentiated Phenotype and Is Required for Thyroid Carcinoma Cell Proliferation J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 928 - 935. [Abstract] [Full Text] [PDF]
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 P. Smyth, S. Finn, S. Cahill, E. O'Regan, R. Flavin, J. J. O'Leary, and O. Sheils ret/PTC and BRAF Act as Distinct Molecular, Time-Dependant Triggers in a Sporadic Irish Cohort of Papillary Thyroid Carcinoma International Journal of Surgical Pathology, January 1, 2005; 13(1): 1 - 8. [Abstract] [PDF]
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A Perren, S Schmid, T Locher, P Saremaslani, C Bonvin, P U Heitz, and P Komminoth BRAF and endocrine tumors: mutations are frequent in papillary thyroid carcinomas, rare in endocrine tumors of the gastrointestinal tract and not detected in other endocrine tumors Endocr. Relat. Cancer, December 1, 2004; 11(4): 855 - 860. [Abstract] [Full Text] [PDF]
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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]
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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]
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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]
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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]
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C. B. Umbricht, G. T. Conrad, D. P. Clark, W. H. Westra, D. C. Smith, M. Zahurak, M. Saji, R. C. Smallridge, S. Goodman, and M. A. Zeiger Human Telomerase Reverse Transcriptase Gene Expression and the Surgical Management of Suspicious Thyroid Tumors Clin. Cancer Res., September 1, 2004; 10(17): 5762 - 5768. [Abstract] [Full Text] [PDF]
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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]
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T. Ikenoue, Y. Hikiba, F. Kanai, J. Aragaki, Y. Tanaka, J. Imamura, T. Imamura, M. Ohta, H. Ijichi, K. Tateishi, et al. Different Effects of Point Mutations within the B-Raf Glycine-Rich Loop in Colorectal Tumors on Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase/Extracellular Signal-Regulated Kinase and Nuclear Factor {kappa}B Pathway and Cellular Transformation Cancer Res., May 15, 2004; 64(10): 3428 - 3435. [Abstract] [Full Text] [PDF]
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Y. Cohen, E. Rosenbaum, S. Begum, D. Goldenberg, C. Esche, O. Lavie, D. Sidransky, and W. H. Westra Exon 15 BRAF Mutations Are Uncommon in Melanomas Arising in Nonsun-Exposed Sites Clin. Cancer Res., May 15, 2004; 10(10): 3444 - 3447. [Abstract] [Full Text] [PDF]
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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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Y. Cohen, E. Rosenbaum, D. P. Clark, M. A. Zeiger, C. B. Umbricht, R. P. Tufano, D. Sidransky, and W. H. Westra Mutational Analysis of BRAF in Fine Needle Aspiration Biopsies of the Thyroid: A Potential Application for the Preoperative Assessment of Thyroid Nodules Clin. Cancer Res., April 15, 2004; 10(8): 2761 - 2765. [Abstract] [Full Text] [PDF]
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M. Xing, V. Vasko, G. Tallini, A. Larin, G. Wu, R. Udelsman, M. D. Ringel, P. W. Ladenson, and D. Sidransky BRAF T1796A Transversion Mutation in Various Thyroid Neoplasms J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1365 - 1368. [Abstract] [Full Text] [PDF]
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M. Xing, Y. Cohen, E. Mambo, G. Tallini, R. Udelsman, P. W. Ladenson, and D. Sidransky Early Occurrence of RASSF1A Hypermethylation and Its Mutual Exclusion with BRAF Mutation in Thyroid Tumorigenesis Cancer Res., March 1, 2004; 64(5): 1664 - 1668. [Abstract] [Full Text] [PDF]
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M. Shinozaki, A. Fujimoto, D. L. Morton, and D. S. B. Hoon Incidence of BRAF Oncogene Mutation and Clinical Relevance for Primary Cutaneous Melanomas Clin. Cancer Res., March 1, 2004; 10(5): 1753 - 1757. [Abstract] [Full Text] [PDF]
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M. Casula, M. Colombino, M. P. Satta, A. Cossu, P. A. Ascierto, G. Bianchi-Scarra, D. Castiglia, M. Budroni, C. Rozzo, A. Manca, et al. BRAF Gene Is Somatically Mutated but Does Not Make a Major Contribution to Malignant Melanoma Susceptibility: The Italian Melanoma Intergroup Study J. Clin. Oncol., January 15, 2004; 22(2): 286 - 292. [Abstract] [Full Text] [PDF]
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 Genetic and Epigenetic Alterations in Cancer Detection: DAVID SIDRANSKY, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196 Toxicol Pathol, January 1, 2004; 32(1): 138 - 139. [PDF]
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T. Ikenoue, Y. Hikiba, F. Kanai, Y. Tanaka, J. Imamura, T. Imamura, M. Ohta, H. Ijichi, K. Tateishi, T. Kawakami, et al. Functional Analysis of Mutations within the Kinase Activation Segment of B-Raf in Human Colorectal Tumors Cancer Res., December 1, 2003; 63(23): 8132 - 8137. [Abstract] [Full Text] [PDF]
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M. N. Nikiforova, E. T. Kimura, M. Gandhi, P. W. Biddinger, J. A. Knauf, F. Basolo, Z. Zhu, R. Giannini, G. Salvatore, A. Fusco, et al. BRAF Mutations in Thyroid Tumors Are Restricted to Papillary Carcinomas and Anaplastic or Poorly Differentiated Carcinomas Arising from Papillary Carcinomas J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5399 - 5404. [Abstract] [Full Text] [PDF]
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A. Calipel, G. Lefevre, C. Pouponnot, F. Mouriaux, A. Eychene, and F. Mascarelli Mutation of B-Raf in Human Choroidal Melanoma Cells Mediates Cell Proliferation and Transformation through the MEK/ERK Pathway J. Biol. Chem., October 24, 2003; 278(43): 42409 - 42418. [Abstract] [Full Text] [PDF]
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F. Cruz III, B. P. Rubin, D. Wilson, A. Town, A. Schroeder, A. Haley, T. Bainbridge, M. C. Heinrich, and C. L. Corless Absence of BRAF and NRAS Mutations in Uveal Melanoma Cancer Res., September 15, 2003; 63(18): 5761 - 5766. [Abstract] [Full Text] [PDF]
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R. Kumar, S. Angelini, K. Czene, I. Sauroja, M. Hahka-Kemppinen, S. Pyrhonen, and K. Hemminki BRAF Mutations in Metastatic Melanoma: A Possible Association with Clinical Outcome Clin. Cancer Res., August 1, 2003; 9(9): 3362 - 3368. [Abstract] [Full Text] [PDF]
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B. G. Wang, H.-Y. Huang, Y.-C. Chen, R. E. Bristow, K. Kassauei, C.-C. Cheng, R. Roden, L. J. Sokoll, D. W. Chan, and I.-M. Shih Increased Plasma DNA Integrity in Cancer Patients Cancer Res., July 15, 2003; 63(14): 3966 - 3968. [Abstract] [Full Text] [PDF]
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Y. Cohen, N. Goldenberg-Cohen, P. Parrella, I. Chowers, S. L. Merbs, J. Pe'er, and D. Sidransky Lack of BRAF Mutation in Primary Uveal Melanoma Invest. Ophthalmol. Vis. Sci., July 1, 2003; 44(7): 2876 - 2878. [Abstract] [Full Text] [PDF]
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