<i>BRAF</i>Alterations in Primary Glial and Glioneuronal Neoplasms of the Central Nervous System With Identification of 2 Novel KIAA1549

Lin, Alex; Rodríguez, Fausto J.; Karajannis, Matthias A.; Williams, Susan; Legault, Geneviève; Zagzag, David; Burger, Peter C.; Allen, Jeffrey C.; Eberhart, Charles G.; Bar, Eli E.

doi:10.1097/nen.0b013e31823f2cb0

Cited by 153 publications

(130 citation statements)

References 30 publications

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“…Gateway cloning (Invitrogen) and site-directed mutagenesis were used to generate the following Myctagged constructs: wild-type BRAF, kinase-dead K482M BRAF mutant (KD), BRAF V600E mutant (V600E), HRASV12 mutant (RASV12), and wild-type KIAA1549. Full-length, "long form" KIAA1549-BRAF fusion (Fusion-1) was generated by translationally silent site-directed mutagenesis, providing restriction sites that permitted the construction of the KIAA1549-BRAF gene fusion via restriction digest/subcloning of the N terminus of KIAA1549 (exons [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] Fig. 1F).…”

Section: Methodsmentioning

confidence: 99%

“…The discovery of an oncogenic KIAA1549-BRAF fusion as a hallmark genetic event in pediatric low-grade astrocytomas suggests that recently developed targeted approaches may offer therapeutic opportunities for BRAF-altered tumors (2)(3)(4). The KIAA1549-BRAF fusion gene forms as a result of an internal, nonrandom tandem duplication event in chromosome 7q34 in which the N terminus of the KIAA1549 gene is fused with the C terminus of BRAF, preserving the BRAF kinase domain.…”

Section: Paradoxical Activation and Raf Inhibitor Resistance Of Braf mentioning

confidence: 99%

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Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas

Sievert

Lang

Boucher

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

247

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Astrocytomas are the most common type of brain tumors in children. Activated BRAF protein kinase mutations are characteristic of pediatric astrocytomas with KIAA1549-BRAF fusion genes typifying low-grade astrocytomas and V600E BRAF alterations characterizing distinct or higher-grade tumors. Recently, BRAF-targeted therapies, such as vemurafenib, have shown great promise in treating V600E-dependent melanomas. Like V600E BRAF, BRAF fusion kinases activate MAPK signaling and are sufficient for malignant transformation; however, here we characterized the distinct mechanisms of action of KIAA1549-BRAF and its differential responsiveness to PLX4720, a first-generation BRAF inhibitor and research analog of vemurafenib. We found that in cells expressing KIAA1549-BRAF, the fusion kinase functions as a homodimer that is resistant to PLX4720 and accordingly is associated with CRAF-independent paradoxical activation of MAPK signaling. Mutagenesis studies demonstrated that KIAA1549-BRAF fusion-mediated signaling is diminished with disruption of the BRAF kinase dimer interface. In addition, the KIAA1549-BRAF fusion displays increased binding affinity to kinase suppressor of RAS (KSR), an RAF relative recently demonstrated to facilitate MEK phosphorylation by BRAF. Despite its resistance to PLX4720, the KIAA1549-BRAF fusion is responsive to a second-generation selective BRAF inhibitor that, unlike vemurafenib, does not induce activation of wild-type BRAF. Our data support the development of targeted treatment paradigms for BRAF-altered pediatric astrocytomas and also demonstrate that therapies must be tailored to the specific mutational context and distinct mechanisms of action of the mutant kinase.

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Section: Methodsmentioning

confidence: 99%

Section: Paradoxical Activation and Raf Inhibitor Resistance Of Braf mentioning

confidence: 99%

Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas

Sievert

Lang

Boucher

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

247

212

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“…The presence of both alterations has been recently reported for a low-grade astrocytoma. 28 As there is only a single such case, the effect of both alterations on tumor behavior, while curious, is not clear.…”

Section: Modern Pathology (2013) 26 1279-1287mentioning

confidence: 99%

“…The presence of other less common activating alterations in BRAF is one possible explanation for our findings. Among the BRAF fusion products reported in pilocytic astrocytoma, 28 we only tested for KIAA1549:BRAF. This raises the possibility that other alterations in BRAF may drive the activation of p-MAPK1 and CDKN2A in pilocytic astrocytoma of the optic nerve.…”

Section: Modern Pathology (2013) 26 1279-1287mentioning

confidence: 99%

Pilocytic astrocytomas of the optic nerve and their relation to pilocytic astrocytomas elsewhere in the central nervous system

et al. 2013

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Pilocytic astrocytoma is a low-grade glioma that affects mostly children and young adults and can occur anywhere in the central nervous system. Pilocytic astrocytoma of the optic nerve is an equally indolent subtype that is occasionally associated with neurofibromatosis type 1. In earlier studies, this subtype was considered within the larger category of 'optic pathway glioma,' which included infiltrating astrocytomas and other hypothalamic tumors. However, there have been suggestions that gliomas in the optic nerve, and especially pilocytic astrocytoma of the optic nerve, are biologically different from tumors within the hypothalamus and other parts of the optic tract. Furthermore, the recent discovery of BRAF duplication and fusion with the KIAA1549 gene is reported to be more typical for posterior fossa tumors, and the rate of this aberration is not well known in pilocytic astrocytoma of the optic nerve. To determine the distinction of pilocytic astrocytoma of the optic nerve from pilocytic astrocytoma of the posterior fossa and to investigate the prevalence of BRAF aberrations, we reviewed the clinicopathological and molecular features of all such patients in our institution. Our study demonstrates that BRAF duplication is more frequent in posterior fossa tumors compared with pilocytic astrocytoma of the optic nerve (P ¼ 0.011). However, the rates of phospho-MAPK1 and CDKN2A expression were high in both pilocytic astrocytoma of the optic nerve and posterior fossa pilocytic astrocytoma, suggesting that the MAPK pathway is active in these tumors. Our study supports the notion that BRAF duplication is more typical of posterior fossa pilocytic astrocytoma and that molecular alterations other than KIAA1549 fusion may underlie MAPK pathway activation in pilocytic astrocytoma of the optic nerve.

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“…However, unlike pilocytic astrocytomas, the rarity and diversity of diffuse PLGGs combined with the scarcity of frozen tissue available for genomic analyses has historically impeded identification of genetic alterations specific to these tumors. Prior studies have found that BRAF-KIAA1549 fusions are rare to nonexistent in diffuse PLGGs, particularly in DA2s (10). Diffuse PLGGs included in large cohorts of low-and high-grade gliomas were suggested to have increased expression of the proto-oncogene v-myb avian myeloblastosis viral oncogene homolog (MYB), including rare cases with genomic aberrations involving the gene (11), but no unifying recurrent genetic events have been identified.…”

mentioning

confidence: 99%

Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factorMYBL1

Ramkissoon¹,

Horowitz

Craig³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Pediatric low-grade gliomas (PLGGs) are among the most common solid tumors in children but, apart from BRAF kinase mutations or duplications in specific subclasses, few genetic driver events are known. Diffuse PLGGs comprise a set of uncommon subtypes that exhibit invasive growth and are therefore especially challenging clinically. We performed high-resolution copy-number analysis on 44 formalin-fixed, paraffin-embedded diffuse PLGGs to identify recurrent alterations. Diffuse PLGGs exhibited fewer such alterations than adult low-grade gliomas, but we identified several significantly recurrent events. The most significant event, 8q13.1 gain, was observed in 28% of diffuse astrocytoma grade IIs and resulted in partial duplication of the transcription factor MYBL1 with truncation of its C-terminal negative-regulatory domain. A similar recurrent deletion-truncation breakpoint was identified in two angiocentric gliomas in the related gene v-myb avian myeloblastosis viral oncogene homolog (MYB) on 6q23.3. Whole-genome sequencing of a MYBL1-rearranged diffuse astrocytoma grade II demonstrated MYBL1 tandem duplication and few other events. Truncated MYBL1 transcripts identified in this tumor induced anchorage-independent growth in 3T3 cells and tumor formation in nude mice. Truncated transcripts were also expressed in two additional tumors with MYBL1 partial duplication. Our results define clinically relevant molecular subclasses of diffuse PLGGs and highlight a potential role for the MYB family in the biology of low-grade gliomas.cancer | aCGH | A-myb

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BRAFAlterations in Primary Glial and Glioneuronal Neoplasms of the Central Nervous System With Identification of 2 Novel KIAA1549

Cited by 153 publications

References 30 publications

Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas

Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas

Pilocytic astrocytomas of the optic nerve and their relation to pilocytic astrocytomas elsewhere in the central nervous system

Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factorMYBL1

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