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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.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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); however, four of four BRAF mutations found in NSCLCs were non-V599 (exons 11 and 15). Interestingly, none of the 3 of 43 cancer cell lines with both BRAF and RAS mutations had a codon 599 BRAF mutation [one each in NSCLC (NRAS and Q61K), colorectal (KRAS and G13D), and ovarian cancer lines (KRAS and G13D; Ref. 2
)]. This (2)
and a subsequent report (3)
provide evidence that BRAF kinase mutations are present in 10% of colon cancers overall and in 31% of mismatch repair-deficient tumors (P < 10-6; Ref. 3
). In the latter series of colon cancers, KRAS and BRAF mutations were mutually exclusive (P < 10-6); our current and previous series have inadequate power to evaluate this interaction.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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90% tumor cells. DNA was isolated after xylene extraction and proteinase K digestion as described previously (6)
.
Mutation Screening and Confirmation.
Genomic DNA was screened for mutations using conformation-sensitive capillary electrophoresis as described previously (2)
. The following intron-based PCR primers were designed to amplify the exons of interest and the associated splice junctions:
KRAS exon2:F-GTGTGACATGTTCTAATATAGTCA.
KRAS exon2:R-GAATGGTCCTGCACCAGTAA.
NRAS exon3:F-GGTGAAACCTGTTTGTTGGA.
NRAS exon3:R-AACCTAAAACCAACTCTTCCCA.
BRAF exon11:F-TCCCTCTCAGGCATAAGGTAA.
BRAF exon11:R-CGAACAGTGAATATTTCCTTTGAT.
BRAF exon15:F-TCATAATGCTTGCTCTGATAGGA.
BRAF exon15:R-GGCCAAAAATTTAATCAGTGGA.
The template consisted of 120 ng of genomic DNA. PCR reactions were performed using standard PCR conditions [95°C x 15 min; 95°C x 45 s, 56°C (RAS) or 58°C (BRAF) x 45 s, 72°C x 45 s, for 40 cycles; then 72°C x 10 min, 50-µl reactions] with fluorescence-labeled primers. We combined 3 µl of tumor PCR product and 3 µl of wild-type PCR product in a total volume of 30 µl of 1 x PCR buffer to ensure heteroduplex formation in the event of allele loss in a tumor. Heteroduplex formation was performed as follows: 96°C for 10 min, 72 cycles of 96°C for 20 s decreasing temperature by 0.5°C/cycle, followed by incubation at 60°C for 30 min, and then cooling to room temperature. The samples were analyzed on an ABI PRISM 3100 automated capillary sequencer under semidenaturing conditions using polymer provided by ABI and optimized run conditions (2) . Data were captured using GeneScan to identify samples with a shift in peak migration relative to a wild-type control, indicating the presence of a putative sequence variation. PCR products selected by the presence of a heteroduplex shift were gel purified and sequenced on the ABI 3100 to confirm the presence of a mutation.
DNA was prepared from 292 NSCLCs, 12 neuroendocrine lung cancers, and 35 melanomas. Amplicons of all four exons (BRAF exons 11 and 15, KRAS exon 2, and NRAS exon 3) were obtained from 158 NSCLCs, 10 neuroendocrine lung cancers, and 33 melanomas (Table 1)
. Data on both BRAF exons were available for 179 NSCLCs, 11 neuroendocrine lung cancers, and 35 melanomas (Table 1)
. Mutation frequencies did not vary significantly when tumors lacking data on one BRAF exon were included in the analysis ("All results" versus "Complete Sets;" Fig. 2
). Tumor DNA from failed reactions was repurified, and a minimum of three attempts was made to amplify the exon. Success rates using DNA from frozen tissue and cell lines were almost 100%, but amplification of DNA from archival material was inconsistent. Of the 165 paraffin-embedded lung tumors, 30 failed to yield any amplifiable DNA, and 54 yielded DNA that could not be amplified using at least one primer pair. In only three paraffin-embedded lung cancers, neither BRAF exon, but both RAS exons, amplified, suggesting that frequent large genomic deletions involving BRAF are an unlikely explanation for these results. PCR failures were not consistently attributed to a specific primer pair, suggesting they are a result of random cross-linking during fixation that interferes with primer annealing.
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RESULTS AND DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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). No NSCLC had both a BRAF and a RAS mutation, but the number of mutations identified in either gene is too small to evaluate a genetic interaction. BRAF mutations were identified in 22 of 35 (63%) melanomas, 1 in exon 11, and the remaining 21 in exon 15 (Fig. 2
and Table 2
). Twenty of 21 exon 15 mutations involved codon 599. One NRAS mutation of uncertain significance (S65C) was identified in a melanoma that also had a BRAF mutation (V599E); no KRAS mutations were identified in the melanomas.
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In this series, we identified five NSCLCs with mutations in BRAF, only one of which involves V599. Taken together with data from the previous study (2) , we have identified nine BRAF mutations in NSCLCs, eight of which are non-V599 (P < 10-7). These data provide a high level of statistical support to the hypothesis that BRAF-related tumorigenesis in NSCLC is qualitatively different from that in melanomas with codon 599 mutations, raising the possibility that therapeutic response to RAF inhibitors may be different in these two tumors types, despite the presence of activating BRAF mutations in both.
Of the 104 adenocarcinomas evaluable for both BRAF exons, two had novel mutations in exon 11. V458L is five codons upstream of the first glycine in the G-loop (Fig. 1)
. It is possible that this leucine residue changes the conformation of the adjacent G-loop (2)
, resulting in activation; however, this remains speculative. The second mutation, K438T, alters the basic residue next to a threonine phosphorylated by AKT (Fig. 1)
. BRAF has three AKT phosphorylation sites: (a) Thr439 is one of two unique to BRAF; (b) the other being Ser428; and (c) Ser364 is conserved in RAF1 (Ref. 7
; Fig. 1
). In vitro alanine substitution at Thr439 leads to BRAF activation through loss of AKT-induced inhibition (7)
, with progressively increased BRAF activity as the additional two sites are mutated. The inhibitory effect of AKT-induced phosphorylation on RAF1 also has been demonstrated (8)
. Thus, K438T, as well as K438Q found in a melanoma as described below, is likely to inhibit AKT-dependent phosphorylation of the adjacent Thr439, as adjacent basic residues are commonly required in AKT Ser/Thr phosphorylation consensus sequences (9)
. These data suggest that transformation-related BRAF activation may occur through multiple mechanisms and that mutations of Thr439, as well as the two additional AKT consensus sites (Ser364 and Ser428; Fig. 1
; Ref. 10
), could play a role in tumorigenesis. Although AKT-BRAF cross-talk has been documented in vitro, to our knowledge, this is the first report of mutations involving this interaction in human cancers.
Fourteen of 147 lung adenocarcinomas had KRAS mutations (Fig. 2)
, all but one in codon 12, the exception being A18T, the significance of which is unknown. Constitutional DNA was not available from this patient; thus, a germ-line polymorphism cannot be excluded. The overall KRAS mutation frequency in this series of lung adenocarcinomas is 10%, lower than the 17% detected in NSCLCs in the previous series (2)
and lower than the frequently cited rate of 30% (11
, 12)
. Multiple studies suggest that the frequency of KRAS mutations in nonsmokers (and dogs) is in the range of 10% (11
, 13, 14, 15)
. We have no information on the smoking status of the patients whose tumors were evaluated in our studies, but a bias toward young nonsmokers might occur because of various factors related to selectivity of referrals to a tertiary care hospital.
In the 117 SCC, we identified one novel mutation in exon 11 (T439P) and two mutations in exon 15 (L596V and V599E). As expected based on the existing literature, we did not identify RAS mutations in SCCs. The exon 15 BRAF mutations are both in the activation segment and cause BRAF activation (2) . However, the exon 11 mutation is novel. This mutation alters Thr439, an AKT phosphorylation site (described above), further supporting the suggestion that transformation-related BRAF activation may occur through multiple mechanisms.
No BRAF or KRAS mutations were identified in the 12 neuroendocrine lung cancers, but two had codon 65 NRAS mutations (20%). Analysis of this mutation in a melanoma (described below) suggests this mutation may not be transforming. There are few data in the literature on the prevalence of NRAS mutations in neuroendocrine lung cancers, and our series is small as well, but additional investigation may be warranted.
Data from the 35 early passage primary melanoma cell lines confirm our previous report that the majority of melanomas have BRAF mutations (63% in this series), predominantly V599 (20 of 22, 91%; Fig. 2
and Table 2
; Ref. 2
). One of the two non-V599 mutations is in exon 15 and is in the adjacent residue (K600E). The other non-V599 mutation is in exon 11 (K438Q), similar to the novel K438T mutation identified in a lung adenocarcinoma. This mutation results in substitution of Lys438, likely required for AKT phosphorylation of the adjacent Thr439, thus likely to be an activating mutation (7
, 8
, 10)
.
No KRAS mutations and one NRAS mutation of unknown significance (S65C) were identified in the 35 melanomas. Specifically, no NRAS codon 61 mutations, reported in 15% of melanoma cell lines (16) , were identified. The codon 65 NRAS mutation was further investigated in three additional melanoma cell lines from the same individual, all derived from axillary lymph node metastases. This mutation (S65C) is not present in the primary tumor nor in a metastatic deposit sampled in June 1983 and is present in only one of two cell lines established from lymph node biopsies performed 2 months later. These data provide evidence that this mutation is not a germ-line polymorphism, nor did it contribute to malignant transformation in this tumor; whether it is important in disease progression is unknown.
In summary, we have confirmed the high prevalence of BRAF mutations in melanoma, shown that BRAF exon 11 and 15 mutations are not a common cause of the MAP kinase pathway activation in NSCLC, and identified four novel BRAF mutations. These mutations provide the first in vivo evidence that activation of BRAF through loss of AKT-induced inhibitory phosphorylation is associated with tumorigenesis, and studies to understand this relationship may uncover additional therapeutic targets. We provide strong statistical evidence that BRAF mutations in NSCLCs are qualitatively different that those in melanoma, with possible therapeutic implications when considering BRAF inhibitors. These results define the frequency of BRAF mutations in NSCLC (2–3%) and in melanomas (>60%). In both cases, future studies will determine whether these BRAF mutations represent promising new therapeutic drug targets for these chemoresistant tumors. Even if the BRAF mutations are rare, as in lung cancer, they may identify a tumor sensitive to targeted therapy, resulting in significantly improved outcomes for the patients that harbor them.
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FOOTNOTES |
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1 Supported by funding from the Abramson Family Cancer Research Institute (to B. L. W.) and Lung Cancer SPORE P50 CA70907 (to J. M.). M. Brose is a General Motors Cancer Research Scholar. 
2 To whom requests for reprints should be addressed, at Abramson Family Cancer Research Institute, BRB II/II, Room 514, 421 Curie Boulevard, Philadelphia, PA 19104. Phone: (215) 898-0247; E-mail: weberb{at}mail.med.upenn.edu
3 The abbreviations used are: NSCLC, non-small cell lung cancer; SCC, squamous cell carcinoma.
Received 10/ 3/02. Accepted 10/15/02.
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REFERENCES |
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R. Somasundaram, R. Swoboda, L. Caputo, L. Otvos, B. Weber, P. Volpe, P. van Belle, S. Hotz, D. E. Elder, F. M. Marincola, et al. Human Leukocyte Antigen-A2-Restricted CTL Responses to Mutated BRAF Peptides in Melanoma Patients. Cancer Res., March 15, 2006; 66(6): 3287 - 3293. [Abstract] [Full Text] [PDF]
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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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S. Toyooka, M. Tokumo, H. Shigematsu, K. Matsuo, H. Asano, K. Tomii, S. Ichihara, M. Suzuki, M. Aoe, H. Date, et al. Mutational and Epigenetic Evidence for Independent Pathways for Lung Adenocarcinomas Arising in Smokers and Never Smokers Cancer Res., February 1, 2006; 66(3): 1371 - 1375. [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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 M. Moore, H. W. Hirte, L. Siu, A. Oza, S. J. Hotte, O. Petrenciuc, F. Cihon, C. Lathia, and B. Schwartz Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors Ann. Onc., October 1, 2005; 16(10): 1688 - 1694. [Abstract] [Full Text] [PDF]
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M. Beeram, A. Patnaik, and E. K. Rowinsky Raf: A Strategic Target for Therapeutic Development Against Cancer J. Clin. Oncol., September 20, 2005; 23(27): 6771 - 6790. [Abstract] [Full Text] [PDF]
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H. Davies, C. Hunter, R. Smith, P. Stephens, C. Greenman, G. Bignell, J. Teague, A. Butler, S. Edkins, C. Stevens, et al. Somatic Mutations of the Protein Kinase Gene Family in Human Lung Cancer Cancer Res., September 1, 2005; 65(17): 7591 - 7595. [Abstract] [Full Text] [PDF]
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Y.-Z. Feng, T. Shiozawa, T. Miyamoto, H. Kashima, M. Kurai, A. Suzuki, and I. Konishi BRAF Mutation in Endometrial Carcinoma and Hyperplasia: Correlation with KRAS and p53 Mutations and Mismatch Repair Protein Expression Clin. Cancer Res., September 1, 2005; 11(17): 6133 - 6138. [Abstract] [Full Text] [PDF]
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J. W. Clark, J. P. Eder, D. Ryan, C. Lathia, and H.-J. Lenz Safety and Pharmacokinetics of the Dual Action Raf Kinase and Vascular Endothelial Growth Factor Receptor Inhibitor, BAY 43-9006, in Patients with Advanced, Refractory Solid Tumors Clin. Cancer Res., August 1, 2005; 11(15): 5472 - 5480. [Abstract] [Full Text] [PDF]
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J.-Z. Qin, J. Ziffra, L. Stennett, B. Bodner, B. K. Bonish, V. Chaturvedi, F. Bennett, P. M. Pollock, J. M. Trent, M. J.C. Hendrix, et al. Proteasome Inhibitors Trigger NOXA-Mediated Apoptosis in Melanoma and Myeloma Cells Cancer Res., July 15, 2005; 65(14): 6282 - 6293. [Abstract] [Full Text] [PDF]
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T. Shimamura, A. M. Lowell, J. A. Engelman, and G. I. Shapiro Epidermal Growth Factor Receptors Harboring Kinase Domain Mutations Associate with the Heat Shock Protein 90 Chaperone and Are Destabilized following Exposure to Geldanamycins Cancer Res., July 15, 2005; 65(14): 6401 - 6408. [Abstract] [Full Text] [PDF]
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S. Dangi and P. Shapiro Cdc2-mediated Inhibition of Epidermal Growth Factor Activation of the Extracellular Signal-regulated Kinase Pathway during Mitosis J. Biol. Chem., July 1, 2005; 280(26): 24524 - 24531. [Abstract] [Full Text] [PDF]
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S. Gysin, S.-H. Lee, N. M. Dean, and M. McMahon Pharmacologic Inhibition of RAF->MEK->ERK Signaling Elicits Pancreatic Cancer Cell Cycle Arrest Through Induced Expression of p27Kip1 Cancer Res., June 1, 2005; 65(11): 4870 - 4880. [Abstract] [Full Text] [PDF]
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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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N. H. Tran, X. Wu, and J. A. Frost B-Raf and Raf-1 Are Regulated by Distinct Autoregulatory Mechanisms J. Biol. Chem., April 22, 2005; 280(16): 16244 - 16253. [Abstract] [Full Text] [PDF]
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M. Beloueche-Babari, L. E. Jackson, N. M.S. Al-Saffar, P. Workman, M. O. Leach, and S. M. Ronen Magnetic Resonance Spectroscopy Monitoring of Mitogen-Activated Protein Kinase Signaling Inhibition Cancer Res., April 15, 2005; 65(8): 3356 - 3363. [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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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. [Abstract] [Full Text] [PDF]
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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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 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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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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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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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. 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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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. 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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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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