Somatic Variant Analysis Identifies Targets for Tailored Therapies in Patients with Vascular Malformations

Abstract

Vascular malformations include various disorders characterized by morphological, structural and/or functional alterations of blood and lymph vessels. Most are sporadic, due to somatic mutations. Here, we report a cohort of patients with sporadic and/or unifocal vascular malformations, in whom we carried out next generation sequencing analysis of a panel of genes associated with vascular malformations. The 115 patients analyzed were from different clinical centres. In 37 patients (32%), we found pathogenic mutations: most of these were gain–of–function mutations in PIK3CA (18%, 21/115) and TEK (13/115, 11%). We also found mutations in GNAQ, CCM2 and PTEN. Identifying pathogenic variants in patients with vascular malformations can help improve management, particularly in cases with activating mutations that cause an increase in cell proliferation. Personalized pharmacological treatment, if possible, is now considered preferable to surgery and can help prevent recurrences, i.e., long–term complications of residual malformation or regrowth of tumors. For instance, rapamycin is currently being investigated for the treatment of various vascular malformations associated with hyperactivation of the phosphoinositide 3–kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway.

Comprehensive targeted next-generation sequencing in patients with slow-flow vascular malformations

“…Consistent with the results of previous studies, [4][5][6] we identi ed three somatic PIK3CA variants (c.1624G>A; p.Glu542Lys, c.1633G>A; p.Glu545Lys, and c.3140A>G; p.His1047Arg) in patients with VM, LM, LVM, and KTS, and eight somatic TEK variants (c.2690A>G; p.Tyr897Cys, c.2689T>C; p.Tyr897His, c.2740C>T; p.Leu914Phe, c.2743C>T; p.Arg915C, c.2752C>T; p.Arg918Cys, c.2753G>T; p.Arg918Leu, and c.3295C>T; p.Arg1099*) in patients with VM.…”

“…Pathogenic variants in TEK were identi ed in 10 patients, of whom 6 harbored variants in the mutational hotspot Leu914. 5 One of the mutations, c.921C>G; p.Tyr307*, was rst identi ed in patients with vascular anomalies and was shown to result in a premature stop codon, a common feature of pathogenic variants. Two of the 14 patients with VMs possessed multiple pathogenic variants in TEK (c.2690A>G; p.Tyr897Cys + c.2752C>T; p.Arg918Cys, and c.2689T>C; p.Tyr897His + c.2753G>T; p.Arg918Leu + c.921C>G; p.Tyr307*).…”

“…3 A number of genetic changes have been identi ed in patients with vascular anomalies, the majority of which occur within two of the major intracellular signaling pathways; namely, the RAS/mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. [4][5][6] Recent studies have shown that the PI3K/AKT/mTOR pathway is typically mutated in patients with SFVMs, raising the possibility that targeted therapy could be a useful treatment strategy. [4][5][6] Indeed, sirolimus, also known as rapamycin, is an allosteric inhibitor of mTOR 7 that has been tested in a monocentric prospective phase II clinical trial for patients with SFVMs that were refractory to standard treatments.…”

“…[4][5][6] Recent studies have shown that the PI3K/AKT/mTOR pathway is typically mutated in patients with SFVMs, raising the possibility that targeted therapy could be a useful treatment strategy. [4][5][6] Indeed, sirolimus, also known as rapamycin, is an allosteric inhibitor of mTOR 7 that has been tested in a monocentric prospective phase II clinical trial for patients with SFVMs that were refractory to standard treatments. 3 Sirolimus was found to be highly effective, resulting in a partial response in all patients, reducing symptoms and increasing quality of life.…”

Venous malformation may be a feature of EXT1‐related hereditary multiple exostoses: A report of two unrelated probands

“…Personalized pharmacological treatment is now considered, which can help prevent recurrence. Rapamycin is currently being investigated for the treatment of various vascular malformations associated with hyperactivation of the phosphoinositide 3‐kinase/protein kinase B/mammalian target of rapamycin pathway (Adams & Ricci, 2019; DeMaio et al, 2022; Paolacci et al, 2020).…”