Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma

Taylor, Kathryn R.; Mackay, Alan; Truffaux, Nathalène; Butterfield, Yaron S.N.; Morozova, Olena; Philippe, Cathy; Castel, David; Grasso, Catherine S.; Vinci, Maria; Carvalho, Diana; Carcaboso, Ángel M.; Torres, Carmen de; Cruz, Ofelia; Mora, Jaume; Entz‐Werlé, Natacha; Ingram, Wendy J.; Monje, Michelle; Hargrave, Darren; Bullock, Alex N.; Puget, Stéphanie; Yip, Stephen; Jones, Chris; Grill, Jacques

doi:10.1038/ng.2925

Cited by 455 publications

(480 citation statements)

References 21 publications

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“…Activating mutations of ACVR1/ALK2 have also been found in about 20% of diffuse intrinsic pontine gliomas (DIPGs) (Buczkowicz et al 2014;Taylor et al 2014). Such mutations were linked to increased phosphorylation of Smad1, 5, and 8, suggesting that, in this type of tumor, activation of BMP Smads has a protumorigenic effect.…”

Section: Diffuse Intrinsic Pontine Gliomamentioning

confidence: 99%

Signaling Receptors for TGF-β Family Members

Heldin

Moustakas

2016

Cold Spring Harb Perspect Biol

572

498

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Transforming growth factor b (TGF-b) family members signal via heterotetrameric complexes of type I and type II dual specificity kinase receptors. The activation and stability of the receptors are controlled by posttranslational modifications, such as phosphorylation, ubiquitylation, sumoylation, and neddylation, as well as by interaction with other proteins at the cell surface and in the cytoplasm. Activation of TGF-b receptors induces signaling via formation of Smad complexes that are translocated to the nucleus where they act as transcription factors, as well as via non-Smad pathways, including the Erk1/2, JNK and p38 MAP kinase pathways, and the Src tyrosine kinase, phosphatidylinositol 3 0 -kinase, and Rho GTPases.

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Section: Diffuse Intrinsic Pontine Gliomamentioning

confidence: 99%

Signaling Receptors for TGF-β Family Members

Heldin

Moustakas

2016

Cold Spring Harb Perspect Biol

572

498

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“…37 Recent studies have also recognised recurrent mutations of the ACVR1 gene in these tumours, thereby highlighting another important difference between gliomas affecting children and adults and a potential target for developing much needed therapies. 15 Taylor et al have identified mutations in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase (ALK), in 21% of DIPG samples. 15 Overall, the researchers identified 11 of 52 DIPG samples (21%)…”

Section: Other Targetsmentioning

confidence: 99%

“…15 Taylor et al have identified mutations in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase (ALK), in 21% of DIPG samples. 15 Overall, the researchers identified 11 of 52 DIPG samples (21%)…”

Section: Other Targetsmentioning

confidence: 99%

Approaches Toward Improving the Prognosis of Pediatric Patients With Glioma: Pursuing Mutant Drug Targets With Emerging Small Molecules

Snape

Warr

2015

Seminars in Pediatric Neurology

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“…Most pediatric gliomas exhibit complex genomic signatures with alterations in copy number, single nucleotide variants (SNVs), and structural rearrangements (Jones and Baker 2014). Specifically, structural variants associated with chromothripsis are common in pediatric high-grade gliomas (Buczkowicz et al 2014;Fontebasso et al 2014;Taylor et al 2014;Wu et al 2014). Whole-genome sequencing of tumor/normal patient samples was carried out as described in Buczkowicz et al (2014).…”

Section: Experimental Validation Of Cgrs In Pediatric Gliomasmentioning

confidence: 99%

Identification of complex genomic rearrangements in cancers using CouGaR

et al. 2016

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The genomic alterations associated with cancers are numerous and varied, involving both isolated and large-scale complex genomic rearrangements (CGRs). Although the underlying mechanisms are not well understood, CGRs have been implicated in tumorigenesis. Here, we introduce CouGaR, a novel method for characterizing the genomic structure of amplified CGRs, leveraging both depth of coverage (DOC) and discordant pair-end mapping techniques. We applied our method to whole-genome sequencing (WGS) samples from The Cancer Genome Atlas and identify amplified CGRs in at least 5.2% (10+ copies) to 17.8% (6+ copies) of the samples. Furthermore, ∼95% of these amplified CGRs contain genes previously implicated in tumorigenesis, indicating the importance and widespread occurrence of CGRs in cancers. Additionally, CouGaR identified the occurrence of ‘chromoplexy’ in nearly 63% of all prostate cancer samples and 30% of all bladder cancer samples. To further validate the accuracy of our method, we experimentally tested 17 predicted fusions in two pediatric glioma samples and validated 15 of these (88%) with precise resolution of the breakpoints via qPCR experiments and Sanger sequencing, with nearly perfect copy count concordance. Additionally, to further help display and understand the structure of CGRs, we have implemented CouGaR-viz, a generic stand-alone tool for visualization of the copy count of regions, breakpoints, and relevant genes.

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Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma

Cited by 455 publications

References 21 publications

Signaling Receptors for TGF-β Family Members

Signaling Receptors for TGF-β Family Members

Approaches Toward Improving the Prognosis of Pediatric Patients With Glioma: Pursuing Mutant Drug Targets With Emerging Small Molecules

Identification of complex genomic rearrangements in cancers using CouGaR

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