Somatic PDGFRB Activating Variants in Fusiform Cerebral Aneurysms.

Area of Science:

• Genetics
• Vascular Biology
• Oncology

Background:

• The genetic underpinnings of intracranial aneurysm formation remain largely unknown.
• Somatic genetic variants, arising after conception, are increasingly recognized in various diseases.
• Platelet-derived growth factor receptor beta (PDGFRB) is crucial for vascular development and homeostasis.

Purpose of the Study:

• To investigate the role of somatic genetic variants in the pathogenesis of intracranial aneurysms.
• To identify novel genetic mechanisms contributing to aneurysm formation.
• To explore potential therapeutic targets for aneurysm treatment.

Main Methods:

• Whole exome sequencing of patient blood and fibroblast samples.
• Analysis of somatic PDGFRB variants in aneurysm tissue specimens.
• Functional assays to assess PDGFRB auto-phosphorylation and downstream signaling pathways (ERK, SRC, AKT).

Main Results:

• A novel, somatic, gain-of-function variant in PDGFRB was identified in a patient with progressive intracranial aneurysms.
• Somatic activating PDGFRB variants were found in 4/6 fusiform aneurysms but not in saccular aneurysms.
• PDGFRB-variant cells exhibited overactive auto-phosphorylation and downstream signaling, responsive to sunitinib.

Conclusions:

• Somatic gain-of-function variants in PDGFRB represent a novel mechanism in the pathophysiology of fusiform cerebral aneurysms.
• These findings highlight PDGFRB as a potential therapeutic target for fusiform aneurysms.
• Targeted therapy with kinase inhibitors, such as sunitinib, may offer a new treatment strategy.