MET somatic activating mutations are responsible for lymphovenous malformation and can be identified using cell-free DNA next generation sequencing liquid biopsy

Palmieri, Maria; Sarno, Laura; Tommasi, Andrea; Currò, Aurora; Doddato, Gabriella; Baldassarri, Margherita; Frullanti, Elisa; Giliberti, Annarita; Fallerini, Chiara; Arzini, Aldo; Pinto, Anna Maria; Vaghi, Massimo; Renieri, Alessandra

doi:10.1016/j.jvsv.2020.07.015

Cited by 7 publications

(5 citation statements)

References 20 publications

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“…Taking advantage of this approach we have previously shown that indeed PIK3CA variants justify a large number of KTS cases [8], while RAS-pathway variants generally underlie AVMs [6]. In addition, unexpectedly, we found that somatic mutations in the MET gene represent the most relevant alterations in LVMs [9].…”

Section: Introductionmentioning

confidence: 79%

Nosological and Theranostic Approach to Vascular Malformation through cfDNA NGS Liquid Biopsy

Serio

Palmieri

Loberti

et al. 2022

JCM

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Several different nosological classifications have been used over time for vascular malformations (VMs) since clinical and pathological signs are largely overlapping. In a large proportion of cases, VMs are generated by somatic mosaicism in key genes, belonging to a few different molecular pathways. Therefore, molecular characterization may help in the understanding of the biological mechanisms related to the development of pathology. Tissue biopsy is not routinely included in the diagnostic path because of the need for fresh tissue specimens and the risk of bleeding. Bypassing the need for bioptic samples, we took advantage of the possibility of isolating cell-free DNA likely released by the affected tissues, to molecularly characterize 53 patients by cfDNA-NGS liquid biopsy. We found a good match between the identified variant and the clinical presentation. PIK3CA variants were found in 67% of Klippel Trenaunay Syndrome individuals; KRAS variants in 60% of arteriovenous malformations; MET was mutated in 75% of lymphovenous malformations. Our results demonstrate the power of cfDNA-NGS liquid biopsy in VMs clinical classification, diagnosis, and treatment. Indeed, tailored repurposing of pre-existing cancer drugs, such as PIK3CA, KRAS, and MET inhibitors, can be envisaged as adjuvant treatment, in addition to surgery and/or endovascular treatment, in the above-defined VMs categories, respectively.

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Section: Introductionmentioning

confidence: 79%

Nosological and Theranostic Approach to Vascular Malformation through cfDNA NGS Liquid Biopsy

Serio

Palmieri

Loberti

et al. 2022

JCM

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“…They were able to identify KRAS mutations (p.G12V and pG12D) in all specimens despite low variant allele frequencies (1.18%–4.19%). This group subsequently conducted several other studies using the same LB technique for VM patients: (1) in one study, they found novel mutations in the MET gene in 4/4 patients with extracranial severe venolymphatic malformations, with a VAF of 0.09%–0.97% ( Palmieri et al, 2021a ); (2) the same year, they published a case series of 7 patients with Klippel-Trenanay syndrome, all of whom harboured mutations in the PIK3CA gene found at a VAF of 0.18%–1.23% in both peripheral and efferent vein samples (albeit higher VAF from efferent vein) ( Palmieri et al, 2021b ); and (3) they later validated their findings in a group of 28 patients with various types of VMs and found mutant positive somatic mutations in the efferent vein of 75% patients with a VAF of 0.07%–6.64% ( Serio et al, 2022 ).…”

Section: Liquid Biopsy Techniques and Applications For Vm Carementioning

confidence: 99%

“…Studies have shown than salting out methods might improve yield compared to silica-based membrane column methods ( Seong et al, 2022 .). Palmieri and others used the MagMax cell-free Total Nucleic Acid Isolation Kit (ThermoFisher Scientific, Waltham, Mass) in all of their studies, which relies on magnetic beads to isolate DNA as opposed to silica membrane methods; this might have supported the cfDNA yield observed from lesional blood ( Palmieri et al, 2020 ; Palmieri et al, 2021a ; Palmieri et al, 2021b ; Serio et al, 2022 ).…”

Section: Liquid Biopsy Techniques and Applications For Vm Carementioning

confidence: 99%

The expansion of liquid biopsies to vascular care: an overview of existing principles, techniques and potential applications to vascular malformation diagnostics

Mansur,

Radovanovic

2024

Front. Genet.

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Vascular malformations are congenital lesions that occur due to mutations in major cellular signalling pathways which govern angiogenesis, cell proliferation, motility, and cell death. These pathways have been widely studied in oncology and are substrates for various small molecule inhibitors. Given their common molecular biology, there is now a potential to repurpose these cancer drugs for vascular malformation care; however, a molecular diagnosis is required in order to tailour specific drugs to the individual patient’s mutational profile. Liquid biopsies (LBs), emerging as a transformative tool in the field of oncology, hold significant promise in this feat. This paper explores the principles and technologies underlying LBs and evaluates their potential to revolutionize the management of vascular malformations. The review begins by delineating the fundamental principles of LBs, focusing on the detection and analysis of circulating biomarkers such as cell-free DNA, circulating tumor cells, and extracellular vesicles. Subsequently, an in-depth analysis of the technological advancements driving LB platforms is presented. Lastly, the paper highlights the current state of research in applying LBs to various vascular malformations, and uses the aforementioned principles and techniques to conceptualize a liquid biopsy framework that is unique to vascular malformation research and clinical care.

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“…Other lymphangiogenic factors such as hepatocyte growth factor (HGF) and retinoic acid agonist 9-cis retinoic acid (9-cRA ) also have therapeutic potential in preclinical models of lymphedema [ 57 – 61 ]. Treatment of cultured lymphatic endothelial cells (LECs) with HGF increases proliferation, migration, and lymphatic tubule formation, independent of the VEGFR-3 pathway [ 62 ]. 9-cRA, a derivative of vitamin A, stimulates LEC differentiation, migration, and collateral lymphatic formation in part by activating fibroblast receptor signaling and by downregulating expression of cell cycle inhibitors P27 and p57 [ 60 , 61 , 63 – 66 ].…”

Section: Systemic Treatments For Secondary Lymphedemamentioning

confidence: 99%

The Future of Lymphedema: Potential Therapeutic Targets for Treatment

Brown

Campbell

Kuonqui

et al. 2023

Curr Breast Cancer Rep

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Purpose of Review This review aims to summarize the current knowledge regarding the pharmacological interventions studied in both experimental and clinical trials for secondary lymphedema. Recent Findings Lymphedema is a progressive disease that results in tissue swelling, pain, and functional disability. The most common cause of secondary lymphedema in developed countries is an iatrogenic injury to the lymphatic system during cancer treatment. Despite its high incidence and severe sequelae, lymphedema is usually treated with palliative options such as compression and physical therapy. However, recent studies on the pathophysiology of lymphedema have explored pharmacological treatments in preclinical and early phase clinical trials. Summary Many potential treatment options for lymphedema have been explored throughout the past two decades including systemic agents and topical approaches to decrease the potential toxicity of systemic treatment. Treatment strategies including lymphangiogenic factors, anti-inflammatory agents, and anti-fibrotic therapies may be used independently or in conjunction with surgical approaches.

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MET somatic activating mutations are responsible for lymphovenous malformation and can be identified using cell-free DNA next generation sequencing liquid biopsy

Cited by 7 publications

References 20 publications

Nosological and Theranostic Approach to Vascular Malformation through cfDNA NGS Liquid Biopsy

Nosological and Theranostic Approach to Vascular Malformation through cfDNA NGS Liquid Biopsy

The expansion of liquid biopsies to vascular care: an overview of existing principles, techniques and potential applications to vascular malformation diagnostics

The Future of Lymphedema: Potential Therapeutic Targets for Treatment

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