Somatic PIK3R1 variation as a cause of vascular malformations and overgrowth

Abstract

Purpose Somatic activating variants in the PI3K-AKT pathway cause vascular malformations with and without overgrowth. We previously reported an individual with capillary and lymphatic malformation harboring a pathogenic somatic variant in PIK3R1, which encodes three PI3K complex regulatory subunits. Here, we investigate PIK3R1 in a large cohort with vascular anomalies and identify an additional 16 individuals with somatic mosaic variants in PIK3R1. Methods Affected tissue from individuals with vascular lesions and overgrowth recruited from a multisite collaborative network was studied. Next-generation sequencing targeting coding regions of cell-signaling and cancer-associated genes was performed followed by assessment of variant pathogenicity. Results The phenotypic and variant spectrum associated with somatic variation in PIK3R1 is reported herein. Variants occurred in the inter-SH2 or N-terminal SH2 domains of all three PIK3R1 protein products. Phenotypic features overlapped those of the PIK3CA-related overgrowth spectrum (PROS). These overlapping features included mixed vascular malformations, sandal toe gap deformity with macrodactyly, lymphatic malformations, venous ectasias, and overgrowth of soft tissue or bone. Conclusion Somatic PIK3R1 variants sharing attributes with cancer-associated variants cause complex vascular malformations and overgrowth. The PIK3R1-associated phenotypic spectrum overlaps with PROS. These data extend understanding of the diverse phenotypic spectrum attributable to genetic variation in the PI3K-AKT pathway.

PIK3R1, SPNB2, and CRYAB as Potential Biomarkers for Patients with Diabetes and Developing Acute Myocardial Infarction

“…Phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) can be enhanced by CapG, an additional oncogenic signaling mutation that leads to increased PI3K/Akt activation [ 16 – 18 ]. Somatic PIK3R1 variation can also be attributed to genetic variation in the PI3K-AKT pathway and can induce vascular malformations and overgrowth [ 19 ]. The PI3K δ enzyme complex, including PIK3CD, PIK3R1, or phosphatase and tensin homolog (PTEN), is primarily present in the immune system and comprises a catalytic (p110 δ ) and regulatory (p85 α ) subunit, and both overactivation and underactivation of PI3K δ lead to impaired and dysregulated immunity, for instance, B-cell lymphomas [ 20 , 21 ].…”

Somatic variation as an incidental finding in the pediatric next-generation sequencing era

“…The genomic DNA template derived from peripheral blood was added to Platinum SuperFi II PCR Master Mix (Invitrogen) along with CBL primers (forward (5′-GGAAACAAGTCTTCACTTTT-3′) and reverse (5′-GCTCAATCTTTACATCCTTATC-3′)) and amplified by PCR as previously described ( Cottrell et al 2021 ). Because of limited residual volume associated with the buccal samples, DNA was incorporated into a 50-µL solution of 1× Platinum SuperFi II PCR Master Mix (Invitrogen) and 20 nM CBL primers in the sample tube for 10 min at 37°C.…”

“…Finally, products were purified using 1.8× SPRIselect and used as DNA template in a second round of PCR. Amplified products were purified using 1.5× SPRIselect and processed as described ( Miller et al 2020b ; Cottrell et al 2021 ). Sequencing of the pooled libricons (amplicon libraries; Miller et al 2020b ) occurred on an Illumina iSeq 100.…”

Targeted treatment of vascular anomalies

“…Somatic mutations in PIK3CA, PIK3R1, PIK3R2, AKT1, AKT3, and TEK lead to hyperactivation of the PI3K signaling pathway, which results in abnormal tissue growth, angiogenesis, and lymphangiogenesis. Activating mutations in this pathway have been identified in vascular tumors, vascular malformations, and many disorders associated with tissue overgrowth ( Cottrell et al, 2021 ; Davies et al, 2021 ; Rivière et al, 2012 ).…”

“…No drugs have been approved by the U.S. Food and Drug Administration for treatment, and standardized treatment protocols have not been developed. The use of targeted next-generation sequencing (NGS) has demonstrated that many vascular anomalies are caused by mosaic mutations in highly conserved genes that control cell proliferation and survival ( Cottrell et al, 2021 ; Keppler-Noreuil et al, 2014 ; Lindhurst et al, 2011 ; Madsen et al, 2018 ; Mirzaa et al, 2013 ; Siegel et al, 2018 ). This has transformed our fundamental understanding of the pathobiology of vascular anomalies and, for the first time, revealed potential pharmacologic targets for these disorders.…”