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dc.contributor.authorCalvete, Oriol
dc.contributor.authorGarcia-Pavia, Pablo 
dc.contributor.authorDominguez, Fernando 
dc.contributor.authorMosteiro, Lluc
dc.contributor.authorPérez-Cabornero, Lucía
dc.contributor.authorCantalapiedra, Diego
dc.contributor.authorZorio, Esther
dc.contributor.authorRamón Y Cajal, Teresa
dc.contributor.authorCrespo-Leiro, Maria G
dc.contributor.authorTeulé, Álex
dc.contributor.authorLázaro, Conxi
dc.contributor.authorMorente, Manuel M
dc.contributor.authorUrioste, Miguel 
dc.contributor.authorBenitez , Javier
dc.identifier.citationJ Am Heart Assoc. 2019; 8(18):e012875es_ES
dc.description.abstractBackground Mutations in the POT1 gene explain abnormally long telomeres and multiple tumors including cardiac angiosarcomas (CAS). However, the link between long telomeres and tumorigenesis is poorly understood. Methods and Results Here, we have studied the somatic landscape of 3 different angiosarcoma patients with mutations in the POT1 gene to further investigate this tumorigenesis process. In addition, the genetic landscape of 7 CAS patients without mutations in the POT1 gene has been studied. Patients with CAS and nonfunctional POT1 did not repress ATR (ataxia telangiectasia RAD3-related)-dependent DNA damage signaling and showed a constitutive increase of cell cycle arrest and somatic activating mutations in the VEGF (vascular endothelial growth factor)/angiogenesis pathway (KDR gene). The same observation was made in POT1 mutation carriers with tumors different from CAS and also in CAS patients without mutations in the POT1 gene but with mutations in other genes involved in DNA damage signaling. Conclusions Inhibition of POT1 function and damage-response malfunction activated DNA damage signaling and increased cell cycle arrest as well as interfered with apoptosis, which would permit acquisition of somatic mutations in the VEGF/angiogenesis pathway that drives tumor formation. Therapies based on the inhibition of damage signaling in asymptomatic carriers may diminish defects on cell cycle arrest and thus prevent the apoptosis deregulation that leads to the acquisition of driver mutations.es_ES
dc.description.sponsorshipBenitez’s laboratory is partially funded by Centro de Investigacion (CIBERER), Horizon2020 BRIDGES project, and by the Spanish Ministry of Health supported by Federacion Espanola de Enfermedades Raras (FEDER) funds (PI16/00440). Garcia-Pavia’s group is partially supported by the Instituto de Salud Carlos III (ISCIII) (grants CB16/11/00432 and PI14/0967) and by the Spanish Ministry of Economy and Competitiveness (grant SAF2015-71863-REDT). Garcia-Pavia’s and Crespo-Leiro’s groups are supported by FEDER funds. Urioste’s laboratory is funded by Spanish Ministry of Health supported by FEDER fund (PI14/00459).es_ES
dc.publisherAmerican Heart Association (AHA) es_ES
dc.subjectVEGF/angiogenesis pathwayes_ES
dc.subjectCardiac angiosarcomaes_ES
dc.subjectCell cycle arrestes_ES
dc.subjectDamage responsees_ES
dc.titlePOT1 and Damage Response Malfunction Trigger Acquisition of Somatic Activating Mutations in the VEGF Pathway in Cardiac Angiosarcomases_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución-NoComercial 4.0 Internacional*
dc.contributor.funderCentro de Investigación Biomedica en Red - CIBER
dc.contributor.funderMinisterio de Sanidad y Consumo (España)
dc.contributor.funderEuropean Regional Development Fund 
dc.contributor.funderInstituto de Salud Carlos III 
dc.contributor.funderMinisterio de Economía y Competitividad (España)
dc.identifier.journalJournal of the American Heart Associationes_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Regulación Molecular de la Insuficiencia Cardiacaes_ES
dc.rights.accessRightsopen accesses_ES

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