RAS pathway activation and an oncogenic RAS mutation in sporadic pilocytic astrocytoma

Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Neurology (Impact Factor: 8.29). 11/2005; 65(8):1335-6. DOI: 10.1212/01.wnl.0000180409.78098.d7
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    • "IDH1 mutation has never been described in WHO grade I astrocytoma, which is in agreement with our observation (Table 1; Fig. 2); the same results (IDH1 WT) were obtained for ependymoma. Conversely, somatic mutation analysis in grade I pilocytic astrocytoma over the past 10 years has indicated the presence of a 3 bp insertion within codon 598 of the BRAF (v-raf murine sarcoma viral oncogene homolog B) gene; this resulted in a constitutively active BRAF [14] and a G-to-C transversion at codon 13 of the KRAS (Kirsten rat sarcoma viral oncogene homolog) gene, which led to increased activation of the Ras pathway [15]. Such a distinct molecular pattern and the presence of the IDH1 c.G395A; p.R132H mutation have practical implications and can be used directly to help pathologists distinguish pilocytic astrocytomas (with IDH1 WT status) from diffuse ones [4, 16]. "
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    ABSTRACT: IDH1 (isocitrate dehydrogenase 1) is a potential biomarker and drug target. Genomic and epigenetic data on astrocytoma have demonstrated that the IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Furthermore, recent studies have also indicated that a mutant IDH1 inhibitor induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. As the presence of the p.R132H mutation in the IDH1 gene seems to be a more powerful prognostic marker than O(6)-methylguanine-DNA methyltransferase promoter status, we evaluated the presence of IDH1 mutation in Polish patients with astrocytoma, glioblastoma, oligoastrocytoma, ganglioglioma, oligodendroglioma, and ependymoma. The IDH1 mutation status at codon 132 was determined using a mouse monoclonal antibody specific for the R132H mutation, direct sequencing, and Co-amplification at Lower Denaturation Temperature (COLD) polymerase chain reaction (PCR) high-resolution melting-curve analysis (HRM). Wild-type (WT) IDH1 was detected in cases with a World Health Organization (WHO) grade I astrocytoma. The IDH1 c.G395A; p.R132H mutation was observed in 56 and 94 % of grade II and grade III astrocytoma cases, respectively. Significant differences in the median overall survival were observed in astrocytoma patients grouped on the basis of the presence of IDH1 mutation: survival was 24 months longer in grade II astrocytoma and 12 months longer in glioblastoma. Overall survival was compared between grade II astrocytoma patients with low or high expression of the mutant protein. Interestingly, lower R132H expression correlated with better overall survival. Our results indicate the usefulness of assessing the R132H IDH1 mutation in glioma patients: the presence or absence of the R132H mutation can help pathologists to distinguish pilocytic astrocytomas (IDH1 WT) from diffuse ones (R132H IDH1/WT). Moreover, low IDH1 p.R132H expression was related to better prognosis. This clinical implication appears to be important for personalization of prognosis and treatment by oncologists.
    Molecular Diagnosis & Therapy 08/2013; 18(1):45-53. DOI:10.1007/s40291-013-0050-7 · 2.89 Impact Factor
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    • "A small number of activating point mutations in K-Ras have been reported in PAs (Janzarik et al., 2007; Maltzman et al., 1997; Sharma et al., 2005). However, as previously described, screening of our series did not identify any mutations in exons 2 or 3 of H-, K-or N-Ras (Jones et al., 2008). "
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    ABSTRACT: Pilocytic astrocytomas (PAs), WHO malignancy grade I, are the most frequently occurring central nervous system tumour in 5- to 19-year-olds. Recent reports have highlighted the importance of MAPK pathway activation in PAs, particularly through a tandem duplication leading to an oncogenic BRAF fusion gene. Here, we report two alternative mechanisms resulting in MAPK activation in PAs. Firstly, in striking similarity to the common BRAF fusion, tandem duplication at 3p25 was observed, which produces an in-frame oncogenic fusion between SRGAP3 and RAF1. This fusion includes the Raf1 kinase domain, and shows elevated kinase activity when compared with wild-type Raf1. Secondly, a novel 3 bp insertion at codon 598 in BRAF mimics the hotspot V600E mutation to produce a transforming, constitutively active BRaf kinase. Although these two alterations are not common, they bring the number of cases with an identified 'hit' on the Ras/Raf-signalling pathway to 36 from our series of 44 (82%), confirming its central importance to the development of pilocytic astrocytomas.
    Oncogene 05/2009; 28(20):2119-23. DOI:10.1038/onc.2009.73 · 8.46 Impact Factor
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    • "A novel BRAF activating mutation was recently identified in a single PA, where insertion of three nucleotides in the DNA sequence leads to the addition of a threonine residue close to the mutational hotspot at position 600, conferring constitutive BRAF kinase activation and transforming NIH3T3 fibroblasts (Jones et al., 2009). However, these genetic changes alone do not account for the high percentage of samples with pathway activation identified by an earlier study (Sharma et al., 2005). This suggests that novel mechanisms of MAPK pathway activation, potentially unique to LGAs, may exist. "
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    ABSTRACT: Low-grade astrocytomas (LGAs) are the most common type of brain tumor in children. Until recently, very little was known about the underlying biology and molecular genetics of these tumors. However, within the past year a number of studies have shown that the MAPK pathway is constitutively activated in a high proportion of LGAs. Several genetic aberrations which generate this deregulation of the MAPK pathway have been identified, most notably gene fusions between KIAA1549 and BRAF. In this review we summarize these findings, discuss how these gene fusions may arise and consider possible implications for diagnosis and treatment.
    Journal of Cellular Physiology 01/2009; 222(3):509-14. DOI:10.1002/jcp.21978 · 3.84 Impact Factor
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