2114 Increased PDGFRB and NF-κB Signaling Caused by Highly Prevalent Somatic Mutations in Intracranial Aneurysms

INTRODUCTION: Intracranial aneurysms (IAs) are a high-risk factor for life-threatening subarachnoid hemorrhage. METHODS: We conducted screening for sporadic somatic mutations in 65 IA tissues (54 saccular and 11 fusiform aneurysms) and paired blood samples by whole exome and targeted deep sequencing. RESULTS: We identified sporadic mutations in multiple signaling genes and examined their impact on downstream signaling pathways and gene expression in vitro and an arterial dilatation model in mouse in vivo. We identified 16 genes that were mutated in more than one IA cases, and their mutations as a whole were highly prevalent (92%: 60 out of 65 IAs) among all IA cases examined. In particular, mutations in six genes (PDGFRB, AHNAK, OBSCN, RBM10, CACNA1E, and OR5P3), many of which are linked to the NF-κB signaling pathway, were found commonly between fusiform and saccular IAs at a high prevalence (43% of all IA cases examined). We found that mutant PDGFRBs constitutively activated ERK and NF-κB signaling, enhanced cell motility, and induced inflammation-related gene expression in vitro. Spatial transcriptomics also detected similar changes in IA tissues in vivo. Furthermore, virus-mediated expression of a mutant PDGFRB induced a fusiform-like dilatation of the basilar artery in mice, which was blocked by systemic administration of the tyrosine-kinase inhibitor Sunitinib. CONCLUSIONS: Collectively, this study reveals a high prevalence of somatic mutations in NF-κB signaling pathway-related genes in both fusiform and saccular IAs and opens a new avenue of research toward development of its pharmacological interventions.