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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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C W Wong, Y S Fan, T L Chan, A S W Chan, L C Ho, T K F Ma, the Cancer Genome Project, S T Yuen, and S Y Leung BRAF and NRAS mutations are uncommon in melanomas arising in diverse internal organs J. Clin. Pathol., June 1, 2005; 58(6): 640 - 644. [Abstract] [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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