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


Authors: Agaram, N. P.; Wong, G. C.; Guo, T.; Maki, R. G.; Singer, S.; DeMatteo, R. P.; Besmer, P.; Antonescu, C. R.
Article Title: Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors
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. © 2008 Wiley-Liss, Inc.
Keywords: adolescent; adult; child; controlled study; aged; middle aged; gene mutation; major clinical study; exon; mutation; clinical feature; cancer risk; polymerase chain reaction; gene; gene targeting; gastrointestinal stromal tumor; imatinib; gastrointestinal stromal tumors; proto-oncogene proteins c-kit; receptor, platelet-derived growth factor alpha; genotype; drug resistance, neoplasm; pyrimidines; immunoreactivity; mutational analysis; wild type; protein kinase inhibitors; dna, neoplasm; protein-tyrosine kinases; piperazines; genes, ras; genetic screening; b raf kinase; proto-oncogene proteins b-raf; braf gene; nras gene; small intestine tumor
Journal Title: Genes Chromosomes and Cancer
Volume: 47
Issue: 10
ISSN: 1045-2257
Publisher: Wiley Periodicals, Inc  
Date Published: 2008-10-01
Start Page: 853
End Page: 859
Language: English
DOI: 10.1002/gcc.20589
PUBMED: 18615679
PROVIDER: scopus
PMCID: PMC2902874
DOI/URL:
Notes: --- - "Cited By (since 1996): 52" - "Export Date: 17 November 2011" - "CODEN: GCCAE" - "Source: Scopus"
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MSK Authors
  1. Ronald P DeMatteo
    635 DeMatteo
  2. Narasimhan P Agaram
    142 Agaram
  3. Cristina R Antonescu
    741 Antonescu
  4. Robert Maki
    215 Maki
  5. Samuel Singer
    266 Singer
  6. Tianhua Guo
    22 Guo
  7. Peter Besmer
    113 Besmer
  8. Grace C Wong
    11 Wong