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

Abstract

Recent studies have shown that the PI3K signaling pathway plays an important role in the pathogenesis of slow-ow vascular malformations (SFVMs). Analysis of genetic mutations has advanced our understanding of the mechanisms involved in SFVM pathogenesis and may identify new therapeutic targets. We screened for somatic variants in a cohort of patients with SFVMs using targeted next-generation sequencing. Targeted next-generation sequencing of 29 candidate genes associated with vascular anomalies or with the PI3K signaling pathway was performed on affected tissues from patients with SFVMs. Fifty-nine patients with SFVMs (venous malformations n = 21, lymphatic malformations n = 27, lymphatic venous malformations n = 1, and Klippel-Trenaunay syndrome n = 10) were included in the study. TEK and PIK3CA were the most commonly mutated genes in the study. We detected eight TEK pathogenic variants in 10 samples (16.9%) and three PIK3CA pathogenic variants in 28 samples (47.5%). We also identi ed a pathogenic variant in RASA1 in one sample. In total, 38 of 59 patients (64.4%) with SFVMs harbored pathogenic variants in these three genes involved in the PI3K signaling pathway. Inhibitors of this pathway may prove useful as molecular targeted therapies for SFVMs.

Familial CCM Genes Might Not Be Main Drivers for Pathogenesis of Sporadic CCMs-Genetic Similarity between Cancers and Vascular Malformations

“…Complex and syndromic VMs often result from mosaicism in early developmental stages and can vary in manifestation depending on the timing of the mutation and the cell lineage affected [190,202]. Despite these differences, all GOF PIK3CA-associated VMs share the same pathogenesis as slow-flow VMs (SFVMs), which are frequently caused by GOF PIK3CA mutations [18,190,203]. This has been supported by recent sequencing data in patients with slow-flow VMs [18].…”

“…The transforming potential of PI3K catalytic isoforms was realized decades ago in cancer research [6][7][8], and these isoforms have been defined as oncogenes [8,9]. Somatic GOF PIK3CA point mutations have been frequently described in various cancers as an oncogene [10][11][12][13][14][15], as well as in many forms of vascular anomalies, especially the well-known vascular malformations (VMs) [16][17][18][19][20]. This shared genetic similarity between tumors and vascular anomalies suggests that as benign tumors, VeMs might have similar genetic underpins as cancers caused by the exact same somatic PIK3CA GOF mutations [16,[19][20][21].…”

A randomized, placebo‐controlled study to evaluate safety and pharmacokinetics of ART‐001 with a novel oral pediatric formulation in healthy subjects

“…Part I had a hybrid study design consisting of a placebocontrolled study to evaluate safety, tolerability, and PK of ART-001 in SRD (steps [1][2][3][4][5] and an open-label study to evaluate the food effect (step 6). Part I was conducted by the alternating panel with groups A and B (8 subjects per group).…”

“…1,2 Multiple studies demonstrated that most of the patients with SFVMs have somatic gain-of-function mutations in genes encoding PI3Kα and its upstream or downstream kinases. [3][4][5][6][7] In addition, there is accumulating clinical evidence suggesting the pharmacological inhibition of PI3K/AKT/mTOR pathway (i.e., mTOR inhibitor sirolimus and PI3Kα inhibitor alpelisib) would be a promising approach for the treatment of SFVMs. [8][9][10][11][12] ART-001 (serabelisib, also known as TAK-117) is a novel, orally available, selective PI3Kα inhibitor, originally developed for advanced solid tumors, but is now being developed for the treatment of SFVMs in both the pediatric and adult populations.…”

“…Recent studies revealed that phosphatidylinositol 3‐kinase alpha (PI3Kα)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway plays an important role in the pathogenesis of SFVMs 1,2 . Multiple studies demonstrated that most of the patients with SFVMs have somatic gain‐of‐function mutations in genes encoding PI3Kα and its upstream or downstream kinases 3–7 . In addition, there is accumulating clinical evidence suggesting the pharmacological inhibition of PI3K/AKT/mTOR pathway (i.e., mTOR inhibitor sirolimus and PI3Kα inhibitor alpelisib) would be a promising approach for the treatment of SFVMs 8–12 …”