Oncogenic FAM131B–BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma

Cin, Huriye; Meyer, Claus; Herr, Ricarda; Janzarik, Wibke G.; Lambert, Sally R.; Jones, David; Jacob, Karine; Benner, Axel; Witt, Hendrik; Remke, Marc; Bender, Sebastian; Falkenstein, Fabian; Anh, Ton Nu Van; Olbrich, Heike; Deimling, Andreas von; Pekrun, Arnulf; Kulozik, Andreas E.; Gnekow, Astrid; Scheurlen, Wolfram; Witt, Olaf; Omran, Heymut; Jabado, Nada; Collins, V. Peter; Brummer, Tilman; Marschalek, Rolf; Lichter, Peter; Korshunov, Andrey; Pfister, Stefan M.

doi:10.1007/s00401-011-0817-z

Cited by 213 publications

(233 citation statements)

References 38 publications

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“…Recently, additional RAF fusions have been characterized in low-grade astrocytomas, including a 47-kDa family with sequence similarity 131, member B (FAM131B)-BRAF fusion (9). However, to our knowledge there are no established pediatric low-grade astrocytoma cell lines endogenously expressing BRAF fusions, and indeed very few available pediatric high-grade astrocytoma cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…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%

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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

212

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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: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

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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“…[8][9][10][11][12][13] The biologic significance of BRAF duplication lies in the activation of the MAPK pathway, which can drive tumor proliferation. 9 In addition to KIAA1549:BRAF fusion product, other molecular alterations have been reported in pilocytic astrocytoma, including other BRAF fusion products, 14,15 rare BRAF V600E mutations, 16 BRAF insertions, 17 and KRAS mutations. 18 This list further highlights the critical importance of the MAPK pathway in these tumors.…”

mentioning

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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“…FAM131B (Family with sequence similarity 31 member B) has been found make fusions with BRAF and is involved in some of the cancers like pilocytic astrocytoma 132 . Oncogenic fusions like FAM131B-BRAF are found mostly in brain tumors.…”

Section: Dicationmentioning

confidence: 99%

Revealing ETC-1922159 Affected Unknown 3<em><sup>rd</sup></em> order WNT10B-X-X Combinations, in Silico

Sinha¹

2017

Preprint

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WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. WNTs have been found to directly affect the stemness of the tumor cells via regulation of ASCL2. Switching off the ASCL2 literally blocks the stemness process of the tumor cells and vice versa. Furthermore, recent findings suggest BVES to be highly suppressed in malignancies and in vitro deletions of BVES show higher Wnt signaling activity to induce stemness. WNT10B was found to be highly expressed in such cases. Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be affecting the pathway under certain conditions. For example, WNT10B-ASCL2 is one such 2 nd order combination whose relation needs to be tested under the influence of recently developed porcupine-WNT inhibitor ETC-1922159. The inhibitor is known to suppress PORCN (porcupine) and thus inhibit a range of oncogenes known to be directly or indirectly affected by the Wnts. In a recent unpublished work in bioRxiv, Sinha 1 , we had the opportunity to rank these unknown biological hypotheses for down regulated genes at 2 nd order level after the drug was administered. The in silico observations showed that the combination of WNT10B-ASCL2 was assigned a relatively lower rank, thus validating the pipeline's efficacy with the confirmed wet lab experiment that indicate that both WNT10B and ASCL2 were down regulated after treatment in cancer cells. Here, we take one step further by in silico analysis of the 3 rd order combinations of WNT10B-X-X (X can be known or unknown factor), from a range of 100 randomly picked down regulated genes after ETC-1922159 treatment. The pipeline uses the density based HSIC (Hilbert Schmidt Information Criterion) sensitivity index with an rbf (radial basis function) kernel, which is known to be highly effective in sensitivity analysis. Various unknown/unexplored/untested 3 rd order biological hypotheses emerge some of which are confirmed in wet lab, while others need to be tested. The potential of such ranking is indispensable in the current era of search in a vast combinatorial forest. KEYWORDS -WNT pathway; porcupine inhibitor ETC-1922159; sensitivity analysis; colorectal cancer; unknown biological hypotheses; combinatorial search space; support vector ranking Conference, from 6-11 August 2017, held Significance WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. Often, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be involved in the pathway. The current work reveals at in silico level, the 3rd order WNT10B associated combinations that might be affected by the admin...

show abstract

Oncogenic FAM131B–BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma

Cited by 213 publications

References 38 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

Revealing ETC-1922159 Affected Unknown 3<em><sup>rd</sup></em> order WNT10B-X-X Combinations, in Silico

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