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A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families
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Abstract:
This work is licensed under a Creative Commons Attribution 4.0 International License.-- et al. ; Cardiac angiosarcoma (CAS) is a rare malignant tumour whose genetic basis is unknown. Here we show, by whole-exome sequencing of a TP53-negative Li-Fraumeni-like (LFL) family including CAS cases, that a missense variant (p.R117C) in POT1 (protection of telomeres 1) gene is responsible for CAS. The same gene alteration is found in two other LFL families with CAS, supporting the causal effect of the identified mutation. We extend the analysis to TP53-negative LFL families with no CAS and find the same mutation in a breast AS family. The mutation is recently found once in 121,324 studied alleles in ExAC server but it is not described in any other database or found in 1,520 Spanish controls. In silico structural analysis suggests how the mutation disrupts POT1 structure. Functional and in vitro studies demonstrate that carriers of the mutation show reduced telomere-bound POT1 levels, abnormally long telomeres and increased telomere fragility. ; We are grateful to T. de Lange (The Rockefeller University) and K. Collins (The University of California) for providing POT1 and TPP1 plasmids, respectively. J.B.’s laboratory is partially funded by the Spanish Ministry of Health PI12/00070, the Spanish Ministry of Science and Innovation (INNPRONTA 2012) and the Spanish Research Network on Rare diseases (CIBERER). O.C. is granted by the CIBERER and C.B.-B. by the PI12/00070 supported by FEDER funds. P.G.-P. is partially supported by the Spanish Ministry of Health PI11/0699, PI12/01941 and RD12/0042/0066. M.A.B.’s laboratory is funded with the Spanish Ministry of Science and Innovation, projects SAF2008-05384 and 2007-A-200950 (TELOMARKER), European Research Council Advanced grant GA#232854, the Körber Foundation, Fundación Botín and Fundación Lilly. R.P.’ lab is partially funded by PI11/0949 Supported by FEDER funds. ; Peer Reviewed
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URL: https://doi.org/10.1038/ncomms9383 https://doi.org/10.13039/501100003751 https://doi.org/10.13039/501100004587 https://doi.org/10.13039/501100000781 https://doi.org/10.13039/501100004837 https://doi.org/10.13039/100005595 https://doi.org/10.13039/501100004076 https://doi.org/10.13039/501100006373 https://doi.org/10.13039/501100000780 http://hdl.handle.net/10261/124597
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Interactions between tick and transmitted pathogens evolved to minimise competition through nested and coherent networks
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SIMPLE: a Language for the Specification of Protocols, Similar to Natural Language
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A vector representation of Fluid Construction Grammar using Holographic Reduced Representations
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Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation
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Enological characterization of Spanish Saccharomyces kudriavzevii strains, one of the closest relatives to parental strains of winemaking and brewing Saccharomyces cerevisiae × S. kudriavzevii hybrids
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Upward Refinement for Conceptual Blending in Description Logic — An ASP-based Approach and Case Study in EL++—
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Common genetic variants influence human subcortical brain structures.
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In: ISSN: 0028-0836 ; EISSN: 1476-4679 ; Nature ; https://hal.archives-ouvertes.fr/hal-01196805 ; Nature, Nature Publishing Group, 2015, 520 (7546), pp.224-9. ⟨10.1038/nature14101⟩ (2015)
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Exploring Spanish Health Social Media for detecting drug effects
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Random forest-based prediction of Parkinson's disease progression using acoustic, ASR and intelligibility features
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Depression Awareness and Self-Management Through the Internet: Protocol for an Internationally Standardized Approach
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Applying basic features from sentiment analysis on automatic irony detection
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Translating without In-domain Corpus: Machine TranslationPost-Editing with Online Learning Techniques
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An Empirical Analysis of Data Selection Techniques in Statistical Machine Translation ; Análisis empírico de técnicas de selección de datos en traducción automática estadística
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Developing CALL for heritage languages: The 7 Keys of the Dragon
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Contex-aware gestures for mixed-initiative text editings UIs
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