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(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.




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