Somatic Uniparental Disomy of PTEN in Endothelial Cells Causes Vascular Malformations in Patients with PTEN Hamartoma Tumor Syndrome.

ABSTRACT: PTEN hamartoma tumor syndrome (PHTS) is a rare tumor risk disorder caused by germline loss-of-function mutations in PTEN. Half of these patients develop vascular malformations, a hamartoma characterized by overgrowth of vessels. In this study, we harness biopsies and patient-derived endothelial cells (EC) to study the genetic etiology of PHTS-related vascular malformations. We discover that these lesions are generated by somatic loss of the PTEN wild-type allele through copy-neutral loss of heterozygosity, leading to somatic uniparental disomy of the PTEN-mutated allele in ECs. We established a mouse model of PHTS-related vascular malformations and identified that the mTOR inhibitor rapamycin and AKT inhibitor capivasertib block vascular lesion growth. As proof-of-concept for clinical acti

SUBMITTER: Castillo SD 

PROVIDER: S-EPMC12226217 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature