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Molecular Biology and Genetics |
Department of Medicine [M. S. B., R. G., S. M. A., B. L. W.], Abramson Family Cancer Research Institute [M. S. B., P. V., M. K., I. R., R. G., B. L. W.], University of Pennsylvania Cancer Center; Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania [M. F.]; Department of Pathology, VA Medical Center, The Wistar Institute, Philadelphia, Pennsylvania 19104 [E. E., M. H.]; The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CD10 1SA United Kingdom [H. D., C. C., G. B., P. S., P. A. F., R. W., M. R. S.]; The Hamon Center for Therapeutic Oncology Research, the Departments of Medicine and Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390 [J. M.]; Royal Brompton Hospital, London, SW3 GNP United Kingdom [A. N.]; and Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 [J. A. R.]
BRAF encodes a RAS-regulated kinase that mediates cell growth and malignant transformation kinase pathway activation. Recently, we have identified activating BRAF mutations in 66% of melanomas and a smaller percentage of many other human cancers. To determine whether BRAF mutations account for the MAP kinase pathway activation common in non-small cell lung carcinomas (NSCLCs) and to extend the initial findings in melanoma, we screened DNA from 179 NSCLCs and 35 melanomas for BRAF mutations (exons 11 and 15). We identified BRAF mutations in 5 NSCLCs (3%; one V599 and four non-V599) and 22 melanomas (63%; 21 V599 and 1 non-V599). Three BRAF mutations identified in this study are novel, altering residues important in AKT-mediated BRAF phosphorylation and suggesting that disruption of AKT-induced BRAF inhibition can play a role in malignant transformation. To our knowledge, this is the first report of mutations documenting this interaction in human cancers. Although >90% of BRAF mutations in melanoma involve codon 599 (57 of 60), 8 of 9 BRAF mutations reported to date in NSCLC are non-V599 (89%; P < 10-7), strongly suggesting that BRAF mutations in NSCLC are qualitatively different from those in melanoma; thus, there may be therapeutic differences between lung cancer and melanoma in response to RAF inhibitors. Although uncommon, BRAF mutations in human lung cancers may identify a subset of tumors sensitive to targeted therapy.
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A. J. Canchola, P. L. Horn-Ross, and D. M. Purdie Risk of Second Primary Malignancies in Women with Papillary Thyroid Cancer Am. J. Epidemiol., March 15, 2006; 163(6): 521 - 527. [Abstract] [Full Text] [PDF] |
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M. R. Sapio, D. Posca, G. Troncone, G. Pettinato, L. Palombini, G. Rossi, G. Fenzi, and M. Vitale Detection of BRAF mutation in thyroid papillary carcinomas by mutant allele-specific PCR amplification (MASA) Eur. J. Endocrinol., February 1, 2006; 154(2): 341 - 348. [Abstract] [Full Text] [PDF] |
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O. M. Grbovic, A. D. Basso, A. Sawai, Q. Ye, P. Friedlander, D. Solit, and N. Rosen V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors PNAS, January 3, 2006; 103(1): 57 - 62. [Abstract] [Full Text] [PDF] |
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F. J. Kaye A Curious Link Between Epidermal Growth Factor Receptor Amplification and Survival: Effect of "Allele Dilution" on Gefitinib Sensitivity? J Natl Cancer Inst, May 4, 2005; 97(9): 621 - 623. [Full Text] [PDF] |
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E. Grafstrom, S. Egyhazi, U. Ringborg, J. Hansson, and A. Platz Biallelic Deletions in INK4 in Cutaneous Melanoma Are Common and Associated with Decreased Survival Clin. Cancer Res., April 15, 2005; 11(8): 2991 - 2997. [Abstract] [Full Text] [PDF] |
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H. Gear, H. Williams, E. G. Kemp, and F. Roberts BRAF Mutations in Conjunctival Melanoma Invest. Ophthalmol. Vis. Sci., August 1, 2004; 45(8): 2484 - 2488. [Abstract] [Full Text] [PDF] |
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Y. Lu, D. Bellgrau, L. D. Dwyer-Nield, A. M. Malkinson, R. C. Duke, T. C. Rodell, and A. Franzusoff Mutation-Selective Tumor Remission with Ras-Targeted, Whole Yeast-Based Immunotherapy Cancer Res., August 1, 2004; 64(15): 5084 - 5088. [Abstract] [Full Text] [PDF] |
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M. H. Andersen, J. Fensterle, S. Ugurel, S. Reker, R. Houben, P. Guldberg, T. G. Berger, D. Schadendorf, U. Trefzer, E.-B. Brocker, et al. Immunogenicity of Constitutively Active V599EBRaf Cancer Res., August 1, 2004; 64(15): 5456 - 5460. [Abstract] [Full Text] [PDF] |
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G. Lefevre, A.-L. Glotin, A. Calipel, F. Mouriaux, T. Tran, Z. Kherrouche, C.-A. Maurage, C. Auclair, and F. Mascarelli Roles of Stem Cell Factor/c-Kit and Effects of Glivec(R)/STI571 in Human Uveal Melanoma Cell Tumorigenesis J. Biol. Chem., July 23, 2004; 279(30): 31769 - 31779. [Abstract] [Full Text] [PDF] |
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S. Vicent, M. Garayoa, J. M. Lopez-Picazo, M. D. Lozano, G. Toledo, F. B. J. M. Thunnissen, R. G. Manzano, and L. M. Montuenga Mitogen-Activated Protein Kinase Phosphatase-1 Is Overexpressed in Non-Small Cell Lung Cancer and Is an Independent Predictor of Outcome in Patients Clin. Cancer Res., June 1, 2004; 10(11): 3639 - 3649. [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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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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R H Edwards, M R Ward, H Wu, C A Medina, M S Brose, P Volpe, S Nussen-Lee, H M Haupt, A M Martin, M Herlyn, et al. Absence of BRAF mutations in UV-protected mucosal melanomas J. Med. Genet., April 1, 2004; 41(4): 270 - 272. [Abstract] [Full Text] [PDF] |
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K. Fransen, M. Klintenas, A. Osterstrom, J. Dimberg, H.-J. Monstein, and P. Soderkvist Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas Carcinogenesis, April 1, 2004; 25(4): 527 - 533. [Abstract] [Full Text] [PDF] |
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C. Perlis and M. Herlyn Recent Advances in Melanoma Biology Oncologist, April 1, 2004; 9(2): 182 - 187. [Abstract] [Full Text] [PDF] |
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W. G. Kaelin Jr. Gleevec: Prototype or Outlier? Sci. Signal., March 23, 2004; 2004(225): pe12 - pe12. [Abstract] [Full Text] [PDF] |
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M. S. Sharkey, G. Lizee, M. I. Gonzales, S. Patel, and S. L. Topalian CD4+ T-Cell Recognition of Mutated B-RAF in Melanoma Patients Harboring the V599E Mutation Cancer Res., March 1, 2004; 64(5): 1595 - 1599. [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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K. Omholt, A. Platz, L. Kanter, U. Ringborg, and J. Hansson NRAS and BRAF Mutations Arise Early during Melanoma Pathogenesis and Are Preserved throughout Tumor Progression Clin. Cancer Res., December 15, 2003; 9(17): 6483 - 6488. [Abstract] [Full Text] [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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K. M. Eisenmann, M. W. VanBrocklin, N. A. Staffend, S. M. Kitchen, and H.-M. Koo Mitogen-Activated Protein Kinase Pathway-Dependent Tumor-Specific Survival Signaling in Melanoma Cells through Inactivation of the Proapoptotic Protein Bad Cancer Res., December 1, 2003; 63(23): 8330 - 8337. [Abstract] [Full Text] [PDF] |
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D. Rimoldi, S. Salvi, D. Lienard, F. J. Lejeune, D. Speiser, L. Zografos, and J.-C. Cerottini Lack of BRAF Mutations in Uveal Melanoma Cancer Res., September 15, 2003; 63(18): 5712 - 5715. [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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H. Namba, M. Nakashima, T. Hayashi, N. Hayashida, S. Maeda, T. I. Rogounovitch, A. Ohtsuru, V. A. Saenko, T. Kanematsu, and S. Yamashita Clinical Implication of Hot Spot BRAF Mutation, V599E, in Papillary Thyroid Cancers J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4393 - 4397. [Abstract] [Full Text] [PDF] |
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S. R. Hingorani, M. A. Jacobetz, G. P. Robertson, M. Herlyn, and D. A. Tuveson Suppression of BRAFV599E in Human Melanoma Abrogates Transformation Cancer Res., September 1, 2003; 63(17): 5198 - 5202. [Abstract] [Full Text] [PDF] |
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L. Wang, J. M. Cunningham, J. L. Winters, J. C. Guenther, A. J. French, L. A. Boardman, L. J. Burgart, S. K. McDonnell, D. J. Schaid, and S. N. Thibodeau BRAF Mutations in Colon Cancer Are Not Likely Attributable to Defective DNA Mismatch Repair Cancer Res., September 1, 2003; 63(17): 5209 - 5212. [Abstract] [Full Text] [PDF] |
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T. L. Chan, W. Zhao, Cancer Genome Project, S. Y. Leung, and S. T. Yuen BRAF and KRAS Mutations in Colorectal Hyperplastic Polyps and Serrated Adenomas Cancer Res., August 15, 2003; 63(16): 4878 - 4881. [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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J. Dong, R. G. Phelps, R. Qiao, S. Yao, O. Benard, Z. Ronai, and S. A. Aaronson BRAF Oncogenic Mutations Correlate with Progression rather than Initiation of Human Melanoma Cancer Res., July 15, 2003; 63(14): 3883 - 3885. [Abstract] [Full Text] [PDF] |
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A. Gorden, I. Osman, W. Gai, D. He, W. Huang, A. Davidson, A. N. Houghton, K. Busam, and D. Polsky Analysis of BRAF and N-RAS Mutations in Metastatic Melanoma Tissues Cancer Res., July 15, 2003; 63(14): 3955 - 3957. [Abstract] [Full Text] [PDF] |
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K. Laud, C. Kannengiesser, M.-F. Avril, A. Chompret, D. Stoppa-Lyonnet, L. Desjardins, A. Eychene, F. Demenais, French Hereditary Melanoma Study Group, G. M. Lenoir, et al. BRAF as a Melanoma Susceptibility Candidate Gene? Cancer Res., June 15, 2003; 63(12): 3061 - 3065. [Abstract] [Full Text] [PDF] |
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M. Eskandarpour, J. Hashemi, L. Kanter, U. Ringborg, A. Platz, and J. Hansson Frequency of UV-Inducible NRAS Mutations in Melanomas of Patients With Germline CDKN2A Mutations J Natl Cancer Inst, June 4, 2003; 95(11): 790 - 798. [Abstract] [Full Text] [PDF] |
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