Cancer Discov

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. Here, we harness biopsies and patient-derived endothelial cells (ECs) to study the genetic etiology of PHTS-related vascular malformations. We discover that these lesions are generated by the 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 activity, off-label treatment with rapamycin of two patients with PHTS reduced vascular overgrowth and abrogated lesion-associated pain. Overall, our results uncover the genetic cause of vascular malformations in patients with PHTS and open new avenues for therapeutic intervention.