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

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Genes Chromosomes and Cancer (Impact Factor: 4.04). 10/2008; 47(10):853-9. DOI: 10.1002/gcc.20589
Source: PubMed


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.

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Available from: Peter Besmer, Mar 09, 2015
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    • "Among them, the most intriguing data are those about the findings of IGF1R over-expression in a specific subtype of GIST, having common clinical and molecular hallmarks. In particular, the IGF1R over-expression seems to be limited to pediatric and young-adult GIST, who sharing some pathological and clinical features: the lack of KIT and PDGFRA mutations, the female prevalence, the gastric primary localization, the multifocal presentation, and most frequent lymph nodal involvement and the indolent course of disease even if metastatic (Prakash et al., 2005; Agaram et al., 2008b; Tarn et al., 2008; Pantaleo et al., 2009, 2010; Janeway et al., 2010; Italiano et al., 2012). "
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    ABSTRACT: In the last decades, the concept that Insulin-like Growth Factor (IGF) axis plays a key role in several steps of tumorigenesis, cancer growth and metastasis has been widely documented. The aberration of the IGF system has been described in many kinds of tumours, providing several lines of evidence in support of IGF receptor type 1 (IGF1R) as molecular target in cancer treatment. Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of the gastrointestinal tract, commonly characterized in most cases by KIT and PDGFRA gain mutations. Beyond to the well recognized KIT and PDGFRA gain mutations, in the last years other molecular aberrations have been investigated. Recently, several lines of evidence about the involvement of the IGF system in GIST have been accumulated. The aim of this review is to report all current data about the IGF system involvement in GIST, focusing on the current clinical implication and future perspectives.
    Histology and histopathology 10/2013; 29(2). · 2.10 Impact Factor
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    • "In a small subset of GIST without mutations in KIT and PDGFRA (wild-type (WT)-GIST), other genes are thought to have a role in the tumorigenesis. Mutated genes found in WT-GIST include BRAF (Agaram et al, 2008; Agaimy et al, 2009; Hostein et al, 2010) and succinate dehydrogenase subunits B, C and D (SDHB, SDHC and SDHD) (Pasini et al, 2008; Janeway et al, 2011). "
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    ABSTRACT: Background: Gastrointestinal stromal tumours (GIST) are characterised by high expression of KIT and ETV1, which cooperate in GIST oncogenesis. Our aim was to identify microRNAs that are deregulated in GIST, have a role in GIST pathogenesis, and could potentially be used as therapeutic tool. Methods: Differentially expressed microRNAs between primary GIST (n=50) and gastrointestinal leiomyosarcomas (GI-LMS, n=10) were determined using microarrays. Selected microRNA mimics were transfected into GIST-882 and GIST-T1 cell lines to study the effects of microRNA overexpression on GIST cells. Luciferase reporter assays were used to establish regulation of target genes by selected microRNAs. Results: MiR-17-92 and miR-221/222 cluster members were significantly (P<0.01) lower expressed in GIST vs GI-LMS and normal gastrointestinal control tissues. MiR-17/20a/222 overexpression in GIST cell lines severely inhibited cell proliferation, affected cell cycle progression, induced apoptosis and strongly downregulated protein and – to a lesser extent – mRNA levels of their predicted target genes KIT and ETV1. Luciferase reporter assays confirmed direct regulation of KIT and ETV1 by miR-222 and miR-17/20a, respectively. Conclusion: MicroRNAs that may have an essential role in GIST pathogenesis were identified, in particular miR-17/20a/222 that target KIT and ETV1. Delivering these microRNAs therapeutically could hold great potential for GIST management, especially in imatinib-resistant disease.
    British Journal of Cancer 08/2013; 109(6). DOI:10.1038/bjc.2013.483 · 4.84 Impact Factor
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    • "Mutations in KIT occur most frequently in exon 11, encoding the juxtamembrane domain of the receptor , or in exon 9, which encodes the extracellular dimerization domain, while mutations in the tyrosine kinase domain (exon 18) is the most common PDGRA event (Corless et al., 2011). Recently, mutations in the serine-threonine protein kinase BRAF have also been reported as rare events in GIST (Agaram et al., 2008b; Agaimy et al., 2009; Belinsky et al., 2009; Hostein et al., 2010; Corless et al., 2011). Treatment for advanced GIST has been greatly enhanced by the tyrosine kinase inhibitors (TKI) imatinib mesylate (IM; Gleevec, Novartis) and sunitinib (Sutent, Pfizer), which target the constitutively active mutant isoforms of KIT and PDGFRA. "
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    ABSTRACT: Gastrointestinal stromal tumors (GISTs) in adults are generally driven by somatic gain-of-function mutations in KIT or PDGFRA, and biological therapies targeted to these receptor tyrosine kinases comprise part of the treatment regimen for metastatic and inoperable GISTs. A minority (10-15%) of GISTs in adults, along with ∼85% of pediatric GISTs, lacks oncogenic mutations in KIT and PDGFRA. Not surprisingly these wild type (WT) GISTs respond poorly to kinase inhibitor therapy. A subset of WT GISTs shares a set of distinguishing clinical and pathological features, and a flurry of recent reports has convincingly demonstrated shared molecular characteristics. These GISTs have a distinct transcriptional profile including over-expression of the insulin-like growth factor-1 receptor, and exhibit deficiency in the succinate dehydrogenase (SDH) enzyme complex. The latter is often but not always linked to bi-allelic inactivation of SDH subunit genes, particularly SDHA. This review will summarize the molecular, pathological, and clinical connections that link this group of SDH-deficient neoplasms, and offer a view toward understanding the underlying biology of the disease and the therapeutic challenges implicit to this biology.
    Frontiers in Oncology 05/2013; 3:117. DOI:10.3389/fonc.2013.00117
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