Extracranial Vascular Anomalies Driven by RAS/MAPK Variants: Spectrum and Genotype-Phenotype Correlations

Area of Science:

• Genetics
• Oncology
• Vascular Biology

Background:

• Vascular anomalies encompass a range of conditions, including malformations and tumors.
• The rat sarcoma virus (RAS)/mitogen-activated protein kinase (MAPK) pathway plays a critical role in cellular signaling.
• Dysregulation of the RAS/MAPK pathway has been implicated in various diseases, including cancers and developmental disorders.

Purpose of the Study:

• To investigate the correlation between alterations in the RAS/MAPK pathway and the clinical phenotype of vascular anomalies.
• To explore the potential for improved patient and treatment stratification based on these molecular findings.

Main Methods:

• Retrospective analysis of 29 patients with extracranial vascular anomalies.
• Detection of mosaic pathogenic variants (PVs) in RAS/MAPK pathway genes using targeted gene panel sequencing on tissue DNA.
• Subgroup analyses based on affected genes and phenotypic characteristics.

Main Results:

• Pathogenic variants were identified in Kirsten rat sarcoma viral oncogene, neuroblastoma ras viral oncogene homolog, Harvey rat sarcoma viral oncogene homolog, V-Raf murine sarcoma viral oncogene homolog B, and mitogen-activated protein kinase kinase 1.
• Patients with RAS PVs presented with advanced disease stages (Schobinger stage 3-4) and more frequent post-treatment progression compared to non-RAS PVs.
• Lesions with Kirsten rat sarcoma viral oncogene PVs showed greater infiltration into multiple tissue layers.

Conclusions:

• Specific PVs within the RAS/MAPK pathway are associated with distinct morphological and clinical phenotypes in vascular anomalies.
• RAS variants are linked to more aggressive disease phenotypes.
• These findings provide preliminary data and hypotheses for future, larger-scale investigations into RAS/MAPK pathway-driven vascular anomalies.