Open AccessPOT 1 and Damage Response Malfunction Trigger Acquisition of Somatic Activating Mutations in the VEGF Pathway in Cardiac Angiosarcomas
Author(s) -
Calvete Oriol,
GarciaPavia Pablo,
Domínguez Fernando,
Mosteiro Lluc,
PérezCabornero Lucía,
Cantalapiedra Diego,
Zorio Esther,
Ramón y Cajal Teresa,
CrespoLeiro Maria G.,
Teulé Álex,
Lázaro Conxi,
Morente Manuel M.,
Urioste Miguel,
Benitez Javier
Publication year - 2019
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.119.012875
Subject(s) - dna damage , somatic cell , cancer research , angiogenesis , carcinogenesis , cell cycle , medicine , telomere , mutation , gene mutation , vascular endothelial growth factor , cell cycle checkpoint , biology , gene , cancer , genetics , dna , vegf receptors
Background Mutations in the POT 1 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 POT 1 gene to further investigate this tumorigenesis process. In addition, the genetic landscape of 7 CAS patients without mutations in the POT 1 gene has been studied. Patients with CAS and nonfunctional POT 1 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 POT 1 mutation carriers with tumors different from CAS and also in CAS patients without mutations in the POT 1 gene but with mutations in other genes involved in DNA damage signaling. Conclusions Inhibition of POT 1 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.