Background Mutations in the 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 gene to further investigate this tumorigenesis process. In addition, the genetic landscape of 7 CAS patients without mutations in the gene has been studied. Patients with CAS and nonfunctional 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 ( gene). The same observation was made in mutation carriers with tumors different from CAS and also in CAS patients without mutations in the 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.