Pot1 and damage response malfunction trigger acquisition of somatic activating mutations in the vegf pathway in cardiac angiosarcomas
Calvete, Oriol (Centro de Investigación Biomédica en Red de Enfermedades Raras)
García-Pavía, Pablo (Universidad Francisco de Vitoria)
Domınguez, Fernando (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Mosteiro, Lluc (Centro Nacional de Investigaciones Oncológicas)
Perez Cabornero, Lucía (Parque Tecnologico de Valencia)
Cantalapiedra, Diego (Parque Tecnologico de Valencia)
Zorio, Esther (Hospital Universitari i Politècnic La Fe (València))
Ramon y Cajal, Teresa (Institut d'Investigació Biomèdica Sant Pau)
Crespo-Leiro, Maria Generosa (Instituto de Investigación Biomédica de A Coruña (INIBIC))
Teule, Alex (Hospital Universitari de Bellvitge)
Lazaro Garcia, Conxi (Hospital Universitari de Bellvitge)
Morente, Manuel M. (Centro Nacional de Investigaciones Oncológicas)
Urioste, Miguel (Centro Nacional de Investigaciones Oncológicas)
Benitez, Javier (Centro de Investigación Biomédica en Red de Enfermedades Raras)

Date:	2019
Abstract:	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. 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. 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.
Grants:	Ministerio de Economía y Competitividad PI16/00440 Ministerio de Economía y Competitividad CB16/11/00432 Ministerio de Economía y Competitividad SAF2015-71863-REDT Ministerio de Economía y Competitividad PI14/00459
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Cardiac angiosarcoma ; Cell cycle arrest ; Damage response ; POT1 ; VEGF/angiogenesis pathway
Published in:	Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, Vol. 8 Núm. 18 (2019) , p. e012875, ISSN 2047-9980

DOI: 10.1161/JAHA.119.012875
PMID: 31510873

34 p, 2.3 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles