help button home button Am J Pathol Epitomics, Inc.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Calhoun, E. S.
Right arrow Articles by Kern, S. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Calhoun, E. S.
Right arrow Articles by Kern, S. E.
(American Journal of Pathology. 2003;163:1255-1260.)
© 2003 American Society for Investigative Pathology

BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) Mutations in Distinct Subsets of Pancreatic Cancer

Potential Therapeutic Targets

Eric S. Calhoun*, Jessa B. Jones*, Raheela Ashfaq{dagger}, Volkan Adsay{ddagger}, Suzanne J. Baker§, Virginia Valentine, Paula M. Hempen*, Werner Hilgers||, Charles J. Yeo**, Ralph H. Hruban*{dagger}{dagger} and Scott E. Kern*{dagger}{dagger}

From the Departments of Oncology,* Surgery** and Pathology,{dagger}{dagger} The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland; the Department of Pathology,{dagger} University of Texas Southwestern Medical Center, Dallas, Texas; the Department of Pathology,{ddagger} Harper Hospital and Karmanos Cancer Institute, Wayne State University, Detroit, Michigan; the Departments of Developmental Neurobiology§ and Genetics and Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee; and the Department of Medical Oncology,|| Hospital Saint Louis, Paris, France

The recognition of biologically distinct tumor subsets is fundamental to understanding tumorigenesis. This study investigated the mutational status of the serine/threonine kinase BRAF and the cyclin E regulator FBXW7 (CDC4, FBW7, AGO, SEL10) related to two distinct pancreatic carcinoma subsets: the medullary KRAS2-wild-type and the cyclin E overexpressing tumors, respectively. Among KRAS2-wild-type carcinomas, 33% (3 of 9) contained BRAF V599E mutations; one of which was identified in the pancreatic cancer cell line COLO357. Among 74 KRAS2-mutant carcinomas, no BRAF mutations were identified. Among the KRAS2/BRAF wild-type carcinomas, no mutations within pathway members MEK1, MEK2, ERK1, ERK2, RAP1B, or BAD were found. Using pancreatic cancer microarrays and immunohistochemistry, we determined that 6% (4 of 46 and 5 of 100 in two independent panels) of pancreatic adenocarcinomas overexpress cyclin E. We identified two potential mechanisms for this overexpression including the amplification/gain of CCNE1 gene copies in the Panc-1 and Su86.86 cell lines and a novel somatic homozygous mutation (H460R, in one of 11 pancreatic cancer xenografts having allelic loss) in FBXW7, which was accompanied by cyclin E overexpression by immunohistochemistry. Both BRAF and FBXW7 mutations functionally activate kinase effectors important in pancreatic cancer and extend the potential options for therapeutic targeting of kinases in the treatment of phenotypically distinct pancreatic adenocarcinoma subsets.




This article has been cited by other articles:


Home page
 J. Mol. Diagn.Home page
Z. S. Boyd, R. Raja, S. Johnson, D. A. Eberhard, and M. R. Lackner
A Tumor Sorting Protocol that Enables Enrichment of Pancreatic Adenocarcinoma Cells and Facilitation of Genetic Analyses
J. Mol. Diagn., July 1, 2009; 11(4): 290 - 297.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
S. A. Lang, P. Schachtschneider, C. Moser, A. Mori, C. Hackl, A. Gaumann, D. Batt, H. J. Schlitt, E. K. Geissler, and O. Stoeltzing
Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes
Mol. Cancer Ther., November 1, 2008; 7(11): 3509 - 3518.
[Abstract] [Full Text] [PDF]

Home page
 J. Mol. Diagn.Home page
G. Feldmann and A. Maitra
Molecular Genetics of Pancreatic Ductal Adenocarcinomas and Recent Implications for Translational Efforts
J. Mol. Diagn., March 1, 2008; 10(2): 111 - 122.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
T. Abe, N. Fukushima, K. Brune, C. Boehm, N. Sato, H. Matsubayashi, M. Canto, G. M. Petersen, R. H. Hruban, and M. Goggins
Genome-Wide Allelotypes of Familial Pancreatic Adenocarcinomas and Familial and Sporadic Intraductal Papillary Mucinous Neoplasms
Clin. Cancer Res., October 15, 2007; 13(20): 6019 - 6025.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. Akhoondi, D. Sun, N. von der Lehr, S. Apostolidou, K. Klotz, A. Maljukova, D. Cepeda, H. Fiegl, D. Dofou, C. Marth, et al.
FBXW7/hCDC4 Is a General Tumor Suppressor in Human Cancer
Cancer Res., October 1, 2007; 67(19): 9006 - 9012.
[Abstract] [Full Text] [PDF]

Home page
 Mol Cancer ResHome page
W. Zhang and D. M. Koepp
Fbw7 Isoform Interaction Contributes to Cyclin E Proteolysis
Mol. Cancer Res., December 1, 2006; 4(12): 935 - 943.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
E. S. Calhoun, T. Hucl, E. Gallmeier, K. M. West, D. E. Arking, A. Maitra, C. A. Iacobuzio-Donahue, A. Chakravarti, R. H. Hruban, and S. E. Kern
Identifying Allelic Loss and Homozygous Deletions in Pancreatic Cancer without Matched Normals Using High-Density Single-Nucleotide Polymorphism Arrays
Cancer Res., August 15, 2006; 66(16): 7920 - 7928.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Pathol.Home page
F Bergmann, S Aulmann, M N Wente, R Penzel, I Esposito, J Kleeff, H Friess, and P Schirmacher
Molecular characterisation of pancreatic ductal adenocarcinoma in patients under 40
J. Clin. Pathol., June 1, 2006; 59(6): 580 - 584.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
A. F. Hezel, A. C. Kimmelman, B. Z. Stanger, N. Bardeesy, and R. A. DePinho
Genetics and biology of pancreatic ductal adenocarcinoma.
Genes & Dev., May 15, 2006; 20(10): 1218 - 1249.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. Chen, X. Sun, P. Guo, X.-Y. Dong, P. Sethi, X. Cheng, J. Zhou, J. Ling, J. W. Simons, J. B. Lingrel, et al.
Human Kruppel-like Factor 5 Is a Target of the E3 Ubiquitin Ligase WWP1 for Proteolysis in Epithelial Cells
J. Biol. Chem., December 16, 2005; 280(50): 41553 - 41561.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
S. R. Payne and C. J. Kemp
Tumor suppressor genetics
Carcinogenesis, December 1, 2005; 26(12): 2031 - 2045.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
S. Rottmann, Y. Wang, M. Nasoff, Q. L. Deveraux, and K. C. Quon
From the Cover: A TRAIL receptor-dependent synthetic lethal relationship between MYC activation and GSK3{beta}/FBW7 loss of function
PNAS, October 18, 2005; 102(42): 15195 - 15200.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
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]

Home page
 Cancer Res.Home page
J. Perez-Losada, J.-H. Mao, and A. Balmain
Control of Genomic Instability and Epithelial Tumor Development by the p53-Fbxw7/Cdc4 Pathway
Cancer Res., August 1, 2005; 65(15): 6488 - 6492.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
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]

Home page
 aacredbookHome page
S. I. Reed
Deregulation of Cyclin E in Cancer
Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 53 - 56.
[Full Text] [PDF]

Home page
 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]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2003 by the American Society for Investigative Pathology.