Analyzing the Genetic Spectrum of Vascular Anomalies with Overgrowth via Cancer Genomics

Abstract

Vascular anomalies are variably associated with overgrowth, skeletal anomalies, and abnormalities of the brain, leptomeninges, and eye. We assembled a 16-institution network to determine the range of genetic variants associated with a spectrum of vascular anomalies with overgrowth, ranging from mild to severe. Because of the overlap between cancer-associated variants and previously described somatic variants in vascular overgrowth syndromes, we employed tumor genetic profiling via high-depth next-generation sequencing using a panel to assay affected tissue from a diverse cohort of subjects with vascular anomalies with overgrowth. Seventy-five percent (43/57) harbored pathogenic or likely pathogenic variants in 10 genes. We identified two genes (mTOR, PIK3R1) and several variants previously described in the setting of cancer but that, to our knowledge, have not been described in vascular malformations. All were identified at low variant allele frequency consistent with somatic mosaic etiology. By leveraging somatic variant detection technology typically applied to cancer in a cohort inclusive of broad phenotypic severity, we demonstrated that most vascular anomalies with overgrowth harbor postzygotic gain-of-function mutations in oncogenes. Furthermore, continued interrogation of oncogenes in benign developmental disorders could provide insight into fundamental mechanisms regulating cell growth.

Diagnostic Utility of Next-Generation Sequencing for Disorders of Somatic Mosaicism: A Five-Year Cumulative Cohort

“…Here we present the data derived from our experience in NGS testing of 358 unique specimens from 343 individuals for DoSM over the course of 5 years. Although discrete aspects from 16 case subjects (4.7%) have been reported previously, [9][10][11] this report is a comprehensive review of the aggregate data across the entire cohort. Our findings stress the importance of several factors unique to testing in the somatic setting: multiplexing with broad exonic sequence coverage of multiple gene targets, high unique coverage depth, and directed selection of specimens from diseaseaffected tissue.…”

“…G-protein inhibitor and RAS/RAF pathway inhibitor therapies may prove useful in these people. 11 The 81 individuals with clinical diagnoses listed on test requisitions are described in Table 2. Many of the syndromes represented are caused by specific variants in known genes, for example AKT1 variants in Proteus syndrome, PIK3CA variants in Klippel-Trenaunay syndrome (MIM: 149000), and GNAS variants in McCune Albright syndrome.…”

Treatment of superficial vascular anomalies with topical sirolimus: A multicenter case series

“…Vascular anomalies encompass a heterogeneous group of lesions that are classified based on their biology into tumors or malformations . For many of these vascular anomalies, the genetic basis has been linked to somatic mutations in the PIK3CA/AKT/mTOR signaling pathway causing unregulated activation of angiogenesis and lymphangiogenesis . Such tumors and malformations can result in life‐threatening complications, including local invasion of other structures, coagulopathies, and systemic infections .…”

PHACE syndrome: Infantile hemangiomas associated with multiple congenital anomalies: Clues to the cause

“…Over the past decade, there has been a rapid in expansion in the identification of somatic mutations underlying a wide range of syndromes, especially in the area of vascular and skin anomalies. It has been fascinating that the vast majority of the genes implicated in vascular and skin anomaly syndromes are known oncogenes and tumor suppressor genes, such as Proteus syndrome (AKT1), and the PIK3CA ‐related overgrowth spectrum (PROS syndrome) which includes megalencephaly‐capillary malformation syndrome, Klippel–Trenauanay syndrome, CLOVES syndrome, CLAPO syndrome, and Facial infiltrating lipomatosis syndrome (Keppler‐Noreuil et al, ; Lindhurst et al, ; Mirzaa et al, ; Rivière et al, ; Siegel et al, ). In a large vascular anomaly cohort study, our collaborative network employed a high‐depth next generation sequencing (NGS) panel enriched for genes in cancer‐related pathways to screen for somatic variants in affected tissue.…”

“…In a large vascular anomaly cohort study, our collaborative network employed a high‐depth next generation sequencing (NGS) panel enriched for genes in cancer‐related pathways to screen for somatic variants in affected tissue. Pathogenic or likely pathogenic somatic variants were identified in 75% (43/57) individuals in the following genes: BRAF , GNA11 , GNAQ , KRAS , MAP2K , MTOR , NRAS , PIK3CA , PIK3R1 , and RASA1 (Siegel et al, ). As there are many common features between PHACE syndrome and other syndromes associated with vascular and skin anomalies, we hypothesize that somatic variants in oncogenes or tumor suppressor genes may also play a role in the pathogenesis of PHACE syndrome.…”