Genotype-Phenotype Analysis of Somatic Mutations in Intracranial Arteriovenous Malformations
Dennis J. Konczyk1, Jeremy A. Goss, MD1, August Y. Huang, PhD1, Edward Smith, MD1, Patrick J. Smits, PhD1, Christopher Stapleton, MD2, Aman Patel, MD2, Sanda Alexandrescu, MD1, Matthew L. Warman, MD1, Arin K. Greene, MD MMSc1.
1Boston Children's Hospital, Boston, MA, USA, 2Massachusetts General Hospital, Boston, MA, USA.
BACKGROUND: Intracranial arteriovenous malformation (AVM) is a common cause of hemorrhagic stroke. Lesions typically are sporadic and contain somatic mutations in KRAS or BRAF. The purpose of this study was to identify novel somatic mutations in brain AVMs and to determine if a genotype-phenotype association exists.
METHODS: Human brain AVM specimens (n=18) were collected during a clinically-indicated procedure and subjected to multiplex targeted sequencing using molecular inversion probe (MIP-seq) for mutations in KRAS, BRAF, HRAS, NRAS, and MAP2K1. Endothelial cells (ECs) were separated from non-endothelial cells by immune-affinity purification. Droplet digital PCR (ddPCR) was used to confirm mutations. Patient and AVM characteristics were recorded.
RESULTS: Somatic mutations were confirmed in 10 specimens: KRAS [G12D (n=5), G12V (n=3)] and BRAF [V600E (n=1), Q636X (n=1)]. Mutant alleles were enriched in ECs (n=1) and not present in blood (n=2). Average cohort age was 19 years (range 11-46 years) and 6 patients were female. Presenting symptoms included hemorrhage (n=4), headache (n=4), or seizure (n=2). Average AVM size was 12cm2 (range 1.8cm2-42cm2) and location included parietal (n=2), frontal (n=2), occipital (n=2), temporal (n=2), or parietal-occipital (n=2) lobes. An association between mutation type and clinical characteristics was not present, although the two AVMs containing a BRAF mutation affected the oldest patients in the cohort.
CONCLUSIONS: Sporadic intracranial AVMs contain somatic mutations in KRAS and less commonly BRAF. A genotype-phenotype correlation does not exist between brain AVM mutation type and clinical findings, although BRAF mutations may be associated with later symptom onset.
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