Somatic mosaicism in the MAPK pathway in sporadic brain arteriovenous malformation and association with phenotype

Abstract

OBJECTIVE Sporadic brain arteriovenous malformation (BAVM) is a tangled vascular lesion characterized by direct artery-to-vein connections that can cause life-threatening intracerebral hemorrhage (ICH). Recently, somatic mutations in KRAS have been reported in sporadic BAVM, and mutations in other mitogen-activated protein kinase (MAPK) signaling pathway genes have been identified in other vascular malformations. The objectives of this study were to systematically evaluate somatic mutations in MAPK pathway genes in patients with sporadic BAVM lesions and to evaluate the association of somatic mutations with phenotypes of sporadic BAVM severity. METHODS The authors performed whole-exome sequencing on paired lesion and blood DNA samples from 14 patients with sporadic BAVM, and 295 genes in the MAPK signaling pathway were evaluated to identify genes with somatic mutations in multiple patients with BAVM. Digital droplet polymerase chain reaction was used to validate KRAS G12V and G12D mutations and to assay an additional 56 BAVM samples. RESULTS The authors identified a total of 24 candidate BAVM-associated somatic variants in 11 MAPK pathway genes. The previously identified KRAS G12V and G12D mutations were the only recurrent mutations. Overall, somatic KRAS G12V was present in 14.5% of BAVM lesions and G12D was present in 31.9%. The authors did not detect a significant association between the presence or allelic burden of KRAS mutation and three BAVM phenotypes: lesion size (maximum diameter), age at diagnosis, and age at ICH. CONCLUSIONS The authors confirmed the high prevalence of somatic KRAS mutations in sporadic BAVM lesions and identified several candidate somatic variants in other MAPK pathway genes. These somatic variants may contribute to understanding of the etiology of sporadic BAVM and the clinical characteristics of patients with this condition.

Associated genetic variants and potential pathogenic mechanisms of brain arteriovenous malformation

“…BRAF p.V640E was also detected in a Chinese patient 35. A recent study investigated somatic mosaicism in bAVM tissues among other genes involved in the MAPK pathway, such as CACNA1H , that might affect angiogenesis and vessel stability 39. These findings in bAVM specimens also proved the two hit hypothesis e27 in which environmental factors might cause DNA mutations in ECs, resulting in abnormal proliferation and survival, and finally bAVM develops in a manner similar to tumorigenesis.…”

“…Another candidate gene association study (online supplemental table 2)26 investigated variants that were not evaluated in two or more studies. The remaining 13 studies were case reports27–29 or case series30–39 in which exome sequencing was performed. A specific flowchart demonstrating the process of selection is presented in figure 1.…”

“…The functions and pathways in which EPHA2, 31 EPHB2, 31 STK4, 29 NCoR2, 31 SLIT2, 31 LRP2, 32 PIEZO1, 32 and PRUNE2 32 played a role in the process of bAVM occurrence are shown in online supplemental table 2. Except for these genetic variants, the existence of somatic mosaicism of components in RAS ,34–37 39 BRAC ,34 36 and CACNA1H 39 in the RAS-MAPK signaling pathway, and SMAD9 28 in the BMP/TGF-β signaling pathway, have been reported (online supplemental table 2).…”

“…e47 They are considered to be affected by a variety of environmental factors and contribute to cancer occurrence. Six studies have detected mutations p.G12V and p.G12D in KRAS in human bAVM specimens, but were absent from paired blood samples 34–39. KRAS is an oncogene homolog of the mammalian Ras gene family and encodes a member of the small GTPase superfamily.…”

Emerging pathogenic mechanisms in human brain arteriovenous malformations: a contemporary review in the multiomics era

“…However, mutations in KRAS were the only recurrent mutations in multiple individuals. 56 Many independent groups have focused on these KRAS and related BRAF mutations with targeted analyses such as ddPCR; a recent metanalysis summarizing these works found the prevalence of KRAS and BRAF mutations in bAVMs to be 55% and 7.5%, respectively. 57 How mutations in KRAS influence the clinical presentation or natural history of bAVMs is less clear.…”