Somatic mutations in intracranial arteriovenous malformations

Autoři: Jeremy A. Goss aff001;  August Y. Huang aff002;  Edward Smith aff003;  Dennis J. Konczyk aff001;  Patrick J. Smits aff001;  Christopher L. Sudduth aff001;  Christopher Stapleton aff004;  Aman Patel aff004;  Sanda Alexandrescu aff002;  Matthew L. Warman aff005;  Arin K. Greene aff001
Působiště autorů: Department of Plastic & Oral Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States of America aff001;  Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States of America aff002;  Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States of America aff003;  Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America aff004;  Department of Orthopedic Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States of America aff005
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226852



Intracranial arteriovenous malformation (AVM) is a common cause of primary intracerebral hemorrhage in young adults. Lesions typically are sporadic and contain somatic mutations in KRAS or BRAF. The purpose of this study was to identify somatic mutations in a cohort of participants with brain AVM and to determine if any genotype-phenotype associations exist.


Human brain AVM specimens (n = 16) 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-ECs by immune-affinity purification. Droplet digital PCR (ddPCR) was used to confirm mutations and to screen for mutations that may have been missed by MIP-seq. Patient and AVM characteristics were recorded.


We detected somatic mutations in 10 of 16 specimens (63%). Eight had KRAS mutations [G12D (n = 5), G12V (n = 3)] and two had BRAF mutations [V600E (n = 1), Q636X (n = 1)]. We found no difference in age, sex, presenting symptom, AVM location, or AVM size between patients with a confirmed mutation and those without. Nor did we observe differences in these features between patients with KRAS or BRAF mutations. However, two patients with BRAF mutations presented at an older age than other study participants.


Somatic mutations in KRAS and, less commonly in BRAF, are found in many but not all intracranial AVM samples. Currently, there are no obvious genotype-phenotype correlations that can be used to predict whether a somatic mutation will be detected and, if so, which gene will be mutated.

Klíčová slova:

DNA extraction – Endothelial cells – Gene sequencing – Headaches – Mutation databases – Mutation detection – Nonsense mutation – Somatic mutation


1. Couto JA, Huang AY, Konczyk DJ, Goss JA, Fishman SJ, Mulliken JB, et al. Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation. Am J Hum Genet. 2017;100: 546–554. doi: 10.1016/j.ajhg.2017.01.018 28190454

2. Berman MF, Sciacca RR, Pile-Spellman J, Stapf C, Connolly ES, Mohr JP, et al. The epidemiology of brain arteriovenous malformations [Internet]. Neurosurgery. 2000. pp. 389–397. doi: 10.1097/00006123-200008000-00023 10942012

3. Al-Shahi R, Warlow C. A systematic review of the frequency and prognosis of arteriovenous malformations of the brain in adults. Brain. 2001;124: 1900–26. doi: 10.1093/brain/124.10.1900 11571210

4. McDonald J, Bayrak-Toydemir P, Pyeritz RE. Hereditary hemorrhagic telangiectasia: An overview of diagnosis, management, and pathogenesis. Genetics in Medicine. 2011. pp. 607–616. doi: 10.1097/GIM.0b013e3182136d32 21546842

5. Eerola I, Boon LM, Mulliken JB, Burrows PE, Dompmartin A, Watanabe S, et al. Capillary Malformation–Arteriovenous Malformation, a New Clinical and Genetic Disorder Caused by RASA1 Mutations. Am J Hum Genet. 2003;73: 1240–1249. doi: 10.1086/379793 14639529

6. Revencu N, Boon LM, Mulliken JB, Enjolras O, Cordisco MR, Burrows PE, et al. Parkes Weber syndrome, vein of galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. Hum Mutat. 2008;29: 959–965. doi: 10.1002/humu.20746 18446851

7. Thiex R, Mulliken JB, Revencu N, Boon LM, Burrows PE, Cordisco M, et al. A Novel Association between RASA1 Mutations and Spinal Arteriovenous Anomalies. Am J Neuroradiol. 2010;31: 775–779. doi: 10.3174/ajnr.A1907 20007727

8. Amyere M, Revencu N, Helaers R, Pairet E, Baselga E, Cordisco M, et al. Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling. Circulation. 2017;136: 1037–1048. doi: 10.1161/CIRCULATIONAHA.116.026886 28687708

9. Nikolaev SI, Vetiska S, Bonilla X, Boudreau E, Jauhiainen S, Rezai Jahromi B, et al. Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain. N Engl J Med. 2018;378: 250–261. doi: 10.1056/NEJMoa1709449 29298116

10. Hong T, Yan Y, Li J, Radovanovic I, Ma X, Shao YW, et al. High prevalence of KRAS/BRAF somatic mutations in brain and spinal cord arteriovenous malformations. Brain. 2019;142: 23–34. doi: 10.1093/brain/awy307 30544177

11. Priemer DS, Vortmeyer AO, Zhang S, Chang HY, Curless KL, Cheng L. Activating KRAS mutations in arteriovenous malformations of the brain: frequency and clinicopathologic correlation. Hum Pathol. 2019;89: 33–39. doi: 10.1016/j.humpath.2019.04.004 31026472

12. Luks VL, Kamitaki N, Vivero MP, Uller W, Rab R, Bovee JVMG, et al. Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatr. 2015;166: 1048–1054.e5. doi: 10.1016/j.jpeds.2014.12.069 25681199

13. Tate JG, Bamford S, Jubb HC, Sondka Z, Beare DM, Bindal N, et al. COSMIC: The Catalogue Of Somatic Mutations In Cancer. Nucleic Acids Res. 2019;47: D941–D947. doi: 10.1093/nar/gky1015 30371878

14. Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018;46: D1062–D1067. doi: 10.1093/nar/gkx1153 29165669

15. Pender A, Garcia-Murillas I, Rana S, Cutts RJ, Kelly G, Fenwick K, et al. Efficient genotyping of KRAS mutant non- small cell lung cancer using a multiplexed droplet digital PCR approach. PLoS One. 2015;10. doi: 10.1371/journal.pone.0139074 26413866

16. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363: 809–819. doi: 10.1056/NEJMoa1002011 20818844

17. Yuen ST, Davies H, Chan TL, Ho JW, Bignell GR, Cox C, et al. Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res. 2002;62: 6451–6455. 12438234

18. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417: 949–954. doi: 10.1038/nature00766 12068308

19. Fukushima T, Suzuki S, Mashiko M, Ohtake T, Endo Y, Takebayashi Y, et al. BRAF mutations in papillary carcinomas of the thyroid. Oncogene. 2003;22: 6455–6457. doi: 10.1038/sj.onc.1206739 14508525

20. Cooke SL, Ennis D, Evers L, Dowson S, Chan MY, Paul J, et al. The driver mutational landscape of ovarian squamous cell carcinomas arising in mature cystic teratoma. Clin Cancer Res. 2017;23: 7633–7640. doi: 10.1158/1078-0432.CCR-17-1789 28954785

Článek vyšel v časopise


2019 Číslo 12