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

Autor: Alessandra Renieri, Margherita Baldassarri, Annarita Giliberti, Laura Di Sarno, Elisa Frullanti, Chiara Fallerini, Gabriella Doddato, Andrea Tommasi, Aldo Arzini, Aurora Currò, Anna Maria Pinto, Massimo Vaghi, Maria Palmieri
Rok vydání: 2021
Předmět:
Adult
Male
Pathology
medicine.medical_specialty
Vascular Malformations
Somatic cell
DNA Mutational Analysis
030204 cardiovascular system & hematology
medicine.disease_cause
Risk Assessment
Vascular anomaly
Noninvasive technique
03 medical and health sciences
0302 clinical medicine
Germline mutation
Predictive Value of Tests
Risk Factors
medicine
Activating MET Mutation
Humans
Genetic Predisposition to Disease
Prospective Studies
030212 general & internal medicine
cfDNA
Liquid biopsy
Genetic Association Studies
Mutation
Lymphatic Abnormalities
business.industry
Vascular malformation
Lymphovenous malformation
MET mutation
Liquid Biopsy
High-Throughput Nucleotide Sequencing
Middle Aged
Proto-Oncogene Proteins c-met
medicine.disease
Phenotype
Lymphatic system
Italy
Female
Surgery
Cardiology and Cardiovascular Medicine
business
Cell-Free Nucleic Acids
Zdroj: Journal of Vascular Surgery: Venous and Lymphatic Disorders. 9:740-744
ISSN: 2213-333X
Popis: Objective Germline mutations of either the endothelial cell-specific tyrosine kinase receptor TIE2 or the glomulin (GLMN) gene are responsible for rare inherited venous malformations. Both genes affect the hepatocyte growth factor receptor c-Met, inducing vascular smooth muscle cell migration. Germline mutations of hepatocyte growth factor are responsible for lymphatic malformations, leading to lymphedema. The molecular alteration leading to the abnormal mixed vascular anomaly defined as lymphovenous malformation has remained unknown. Methods A group of 4 patients with lymphovenous malformations were selected. Plasma was obtained from both peripheral and efferent vein samples at the vascular malformation site for cell-free DNA extraction. When possible, we analyzed tissue biopsy samples from the vascular lesion. Results We have demonstrated that in all four patients, an activating MET mutation was present. In three of the four patients, the same pathogenic activating mutation, T1010I, was identified. The mutation was found at the tissue level for the patient with tissue samples available, confirming its causative role in the lymphovenous malformations. Conclusions In the present study, we have demonstrated that cell-free DNA next generation sequencing liquid biopsy is able to identify the MET mutations in affected tissues. Although a wider cohort of patients is necessary to confirm its causative role in lymphovenous malformations, these data suggest that lymphovenous malformations could result from postzygotic somatic mutations in genes that are key regulators of lymphatic development. The noninvasiveness of the method avoids any risk of bleeding and can be easily performed in children. We are confident that the present pioneering results have provided a viable alternative in the future for lymphovenous malformation diagnosis, allowing for subsequent therapy tailored to the genetic defect.
Databáze: OpenAIRE
Externí odkaz: