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[Cancer Research 62, 6997-7000, December 1, 2002]
© 2002 American Association for Cancer Research

Molecular Biology and Genetics

BRAF and RAS Mutations in Human Lung Cancer and Melanoma1

Marcia S. Brose, Patricia Volpe, Michael Feldman, Madhu Kumar, Irum Rishi, Renee Gerrero, Eugene Einhorn, Meenhard Herlyn, John Minna, Andrew Nicholson, Jack A. Roth, Steven M. Albelda, Helen Davies, Charles Cox, Graham Brignell, Philip Stephens, P. Andrew Futreal, Richard Wooster, Michael R. Stratton and Barbara L. Weber2

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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Clin. Cancer Res., April 15, 2005; 11(8): 2991 - 2997.
[Abstract] [Full Text] [PDF]

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 JCOHome page
W. Pao and V. A. Miller
Epidermal Growth Factor Receptor Mutations, Small-Molecule Kinase Inhibitors, and Non-Small-Cell Lung Cancer: Current Knowledge and Future Directions
J. Clin. Oncol., April 10, 2005; 23(11): 2556 - 2568.
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 Cancer Res.Home page
A. Sharma, N. R. Trivedi, M. A. Zimmerman, D. A. Tuveson, C. D. Smith, and G. P. Robertson
Mutant V599EB-Raf Regulates Growth and Vascular Development of Malignant Melanoma Tumors
Cancer Res., March 15, 2005; 65(6): 2412 - 2421.
[Abstract] [Full Text] [PDF]

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 Cold Spring Harb Symp Quant BiolHome page
H. VARMUS, W. PAO, K. POLITI, K. PODSYPANINA, and Y.-C.N. DU
Oncogenes Come of Age
Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 1 - 9.
[Abstract] [PDF]

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 Cold Spring Harb Symp Quant BiolHome page
R.K. THOMAS, H. GREULICH, Y. YUZA, J.C. LEE, T. TENGS, W. FENG, T.-H. CHEN, E. NICKERSON, J. SIMONS, M. EGHOLM, et al.
Detection of Oncogenic Mutations in the EGFR Gene in Lung Adenocarcinoma with Differential Sensitivity to EGFR Tyrosine Kinase Inhibitors
Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 73 - 81.
[Abstract] [PDF]

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 Cancer Res.Home page
M. Bentires-Alj, J. G. Paez, F. S. David, H. Keilhack, B. Halmos, K. Naoki, J. M. Maris, A. Richardson, A. Bardelli, D. J. Sugarbaker, et al.
Activating Mutations of the Noonan Syndrome-Associated SHP2/PTPN11 Gene in Human Solid Tumors and Adult Acute Myelogenous Leukemia
Cancer Res., December 15, 2004; 64(24): 8816 - 8820.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
T. Yamaguchi, D. P. Wallace, B. S. Magenheimer, S. J. Hempson, J. J. Grantham, and J. P. Calvet
Calcium Restriction Allows cAMP Activation of the B-Raf/ERK Pathway, Switching Cells to a cAMP-dependent Growth-stimulated Phenotype
J. Biol. Chem., September 24, 2004; 279(39): 40419 - 40430.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
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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 Cancer Res.Home page
D. Tsavachidou, M. L. Coleman, G. Athanasiadis, S. Li, J. D. Licht, M. F. Olson, and B. L. Weber
SPRY2 Is an Inhibitor of the Ras/Extracellular Signal-Regulated Kinase Pathway in Melanocytes and Melanoma Cells with Wild-Type BRAF but Not with the V599E Mutant
Cancer Res., August 15, 2004; 64(16): 5556 - 5559.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
J. T. Huntington, J. M. Shields, C. J. Der, C. A. Wyatt, U. Benbow, C. L. Slingluff Jr., and C. E. Brinckerhoff
Overexpression of Collagenase 1 (MMP-1) Is Mediated by the ERK Pathway in Invasive Melanoma Cells: ROLE OF BRAF MUTATION AND FIBROBLAST GROWTH FACTOR SIGNALING
J. Biol. Chem., August 6, 2004; 279(32): 33168 - 33176.
[Abstract] [Full Text] [PDF]

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 IOVSHome page
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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 Cancer Res.Home page
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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 Cancer Res.Home page
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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 J. Biol. Chem.Home page
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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 Clin. Cancer Res.Home page
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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 Cancer Res.Home page
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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 J. Med. Genet.Home page
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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 CarcinogenesisHome page
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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 The OncologistHome page
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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 Sci SignalHome page
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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 Cancer Res.Home page
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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 Clin. Cancer Res.Home page
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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 JCOHome page
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.
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 Clin. Cancer Res.Home page
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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 Cancer Res.Home page
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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 Cancer Res.Home page
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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 Cancer Res.Home page
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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 Cancer Res.Home page
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.
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 J. Clin. Endocrinol. Metab.Home page
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.
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 Cancer Res.Home page
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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 Cancer Res.Home page
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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 Cancer Res.Home page
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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 Clin. Cancer Res.Home page
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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 Cancer Res.Home page
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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 Cancer Res.Home page
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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 Cancer Res.Home page
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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 JNCI J Natl Cancer InstHome page
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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