Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors

Agaram, N. P., Wong, G. C., Guo, T., Maki, R. G., Singer, S., Dematteo, R. P., Besmer, P., Antonescu, C. R. (October 2008) Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer, 47 (10). pp. 853-9. ISSN 1098-2264 (Electronic)1045-2257 (Linking)

URL: https://www.ncbi.nlm.nih.gov/pubmed/18615679
DOI: 10.1002/gcc.20589

Abstract

BRAF and NRAS are commonly mutated in cancer and represent the most frequent genetic events in malignant melanoma. More recently, a subset of melanomas was shown to overexpress KIT and harbor KIT mutations. Although most gastrointestinal stromal tumors (GISTs) exhibit activating mutations in either KIT or PDGFRA, about 10% of the cases lack mutations in these genes. It is our hypothesis following the melanoma model that mutations in BRAF or NRAS may play a role in wild-type GIST pathogenesis. Alterations in RAS/MEK/ERK pathway may also be involved in development of imatinib resistance in GIST, particularly in tumors lacking secondary KIT or PDGFRA mutations. Imatinib-naive wild-type GISTs from 61 patients, including 15 children and 28 imatinib-resistant tumors without secondary KIT mutations were analyzed. Screening for hot spots mutations in BRAF (exons 11 and 15) and NRAS (exons 2 and 3) was performed. A BRAF exon 15 V600E was identified in 3 of 61 GIST patients, who shared similar clinical features, being 49- to 55-years-old females and having their tumors located in the small bowel. The tumors were strongly KIT immunoreactive and had a high risk of malignancy. An identical V600E BRAF mutation was also identified in one of 28 imatinib resistant GIST lacking a defined mechanism of drug resistance. In conclusion, we identified a primary BRAF V600E mutations in 7% of adult GIST patients, lacking KIT/PDGFRA mutations. The BRAF-mutated GISTs show predilection for small bowel location and high risk of malignancy. A secondary V600E BRAF mutation could represent an alternative mechanism of imatinib resistance. Kinase inhibitors targeting BRAF may be effective therapeutic options in this molecular GIST subset.

Item Type: Paper
Uncontrolled Keywords: Adult Aged Benzamides Child DNA, Neoplasm/genetics Drug Resistance, Neoplasm/*genetics Female Gastrointestinal Stromal Tumors/*drug therapy/*genetics Genes, ras/genetics Genotype Humans Imatinib Mesylate Male Middle Aged Mutation/*genetics Piperazines/*therapeutic use Polymerase Chain Reaction Prognosis Protein Kinase Inhibitors/*therapeutic use Protein-Tyrosine Kinases/antagonists & inhibitors Proto-Oncogene Proteins B-raf/*genetics Proto-Oncogene Proteins c-kit/genetics Pyrimidines/*therapeutic use Receptor, Platelet-Derived Growth Factor alpha/genetics
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > BRAF
diseases & disorders > cancer > drugs and therapies
diseases & disorders > cancer > cancer types > gastrointestinal stromal tumors
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
diseases & disorders > cancer > prognosis
CSHL Authors:
Communities: CSHL labs > Maki lab
Depositing User: Matt Covey
Date: October 2008
Date Deposited: 26 Oct 2016 17:05
Last Modified: 26 Oct 2016 17:05
PMCID: PMC2902874
Related URLs:
URI: http://repository.cshl.edu/id/eprint/33682

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