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)
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: | https://repository.cshl.edu/id/eprint/33682 |
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