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

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  • 1 Departments of Anesthesia and Perioperative Care,
  • | 2 Neurological Surgery,
  • | 3 Radiology,
  • | 4 Pathology,
  • | 5 Neurology,
  • | 6 Pediatrics, and
  • | 7 Epidemiology and Biostatistics,
  • | 8 Center for Cerebrovascular Research, and
  • | 9 Institute for Human Genetics, University of California, San Francisco, California;
  • | 10 NorthShore University Health System, Evanston, Illinois; and
  • | 11 Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona
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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.

ABBREVIATIONS

BAVM = brain arteriovenous malformation; ddPCR = digital droplet polymerase chain reaction; GATK = Genome Analysis Toolkit; ICH = intracerebral hemorrhage; MAPK = mitogen-activated protein kinase; OCT = optimal cutting temperature; PI = proportional increase; SNV = single-nucleotide variant; TLOD = theta logarithm of the odds; UCSF = University of California, San Francisco; WES = whole-exome sequencing.

Supplementary Materials

    • Supplemental Tables and Figures (PDF 802 KB)

Illustration from Schneider et al. (pp 205–214). Copyright Elyssa Siegel. Published with permission.

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  • 1

    Berman MF, Sciacca RR, Pile-Spellman J, et al. The epidemiology of brain arteriovenous malformations. Neurosurgery. 2000;47(2):389397.

  • 2

    Gabriel RA, Kim H, Sidney S, et al. Ten-year detection rate of brain arteriovenous malformations in a large, multiethnic, defined population. Stroke. 2010;41(1):2126.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Friedlander RM. Clinical practice. Arteriovenous malformations of the brain. N Engl J Med. 2007;356(26):27042712.

  • 4

    Kim H, Al-Shahi Salman R, McCulloch CE, et al. Untreated brain arteriovenous malformation: patient-level meta-analysis of hemorrhage predictors. Neurology. 2014;83(7):590597.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Kim H, Pawlikowska L, Su H, Young WL. Genetics and vascular biology of brain vascular malformations (Chapter 12). In: Grotta JC, Albers GW, Broderick JP, et al. eds. Stroke: Pathophysiology, Diagnosis, and Management. 6th ed. Churchill Livingstone Elsevier; 2016:149162.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    Solomon RA, Connolly ES Jr. Arteriovenous malformations of the brain. N Engl J Med. 2017;377(5):498.

  • 7

    Rutledge WC, Abla AA, Nelson J, et al. Treatment and outcomes of ARUBA-eligible patients with unruptured brain arteriovenous malformations at a single institution. Neurosurg Focus. 2014;37(3):E8.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Potts MB, Lau D, Abla AA, et al. Current surgical results with low-grade brain arteriovenous malformations. J Neurosurg. 2015;122(4):912920.

  • 9

    van Beijnum J, van der Worp HB, Buis DR, et al. Treatment of brain arteriovenous malformations: a systematic review and meta-analysis. JAMA. 2011;306(18):20112019.

  • 10

    Limaye N, Wouters V, Uebelhoer M, et al. Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations. Nat Genet. 2009;41(1):118124.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Macmurdo CF, Wooderchak-Donahue W, Bayrak-Toydemir P, et al. RASA1 somatic mutation and variable expressivity in capillary malformation/arteriovenous malformation (CM/AVM) syndrome. Am J Med Genet A. 2016;170(6):14501454.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Limaye N, Kangas J, Mendola A, et al. Somatic activating PIK3CA mutations cause venous malformation. Am J Hum Genet. 2015;97(6):914921.

  • 13

    Akers AL, Johnson E, Steinberg GK, et al. Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis. Hum Mol Genet. 2009;18(5):919930.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Shirley MD, Tang H, Gallione CJ, et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med. 2013;368(21):19711979.

  • 15

    Soblet J, Limaye N, Uebelhoer M, et al. Variable somatic TIE2 mutations in half of sporadic venous malformations. Mol Syndromol. 2013;4(4):179183.

  • 16

    Nikolaev SI, Vetiska S, Bonilla X, et al. Somatic activating KRAS mutations in arteriovenous malformations of the brain. N Engl J Med. 2018;378(3):250261.

  • 17

    Hong T, Yan Y, Li J, et al. High prevalence of KRAS/BRAF somatic mutations in brain and spinal cord arteriovenous malformations. Brain. 2019;142(1):2334.

  • 18

    Al-Olabi L, Polubothu S, Dowsett K, et al. Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy. J Clin Invest. 2018;128(4):14961508.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Goss JA, Huang AY, Smith E, et al. Somatic mutations in intracranial arteriovenous malformations. PLoS One. 2019;14(12):e0226852.

  • 20

    Priemer DS, Vortmeyer AO, Zhang S, et al. Activating KRAS mutations in arteriovenous malformations of the brain: frequency and clinicopathologic correlation. Hum Pathol. 2019;89:3339.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Oka M, Kushamae M, Aoki T, et al. KRAS G12D or G12V mutation in human brain arteriovenous malformations. World Neurosurg. 2019;126:e1365e1373.

  • 22

    Ayturk UM, Couto JA, Hann S, et al. Somatic activating mutations in GNAQ and GNA11 are associated with congenital hemangioma. Am J Hum Genet. 2016;98(6):1271.

  • 23

    Couto JA, Vivero MP, Kozakewich HP, et al. A somatic MAP3K3 mutation is associated with verrucous venous malformation. Am J Hum Genet. 2015;96(3):480486.

  • 24

    Couto JA, Huang AY, Konczyk DJ, et al. Somatic MAP2K1 mutations are associated with extracranial arteriovenous malformation. Am J Hum Genet. 2017;100(3):546554.

  • 25

    Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(14):17541760.

  • 26

    McKenna A, Hanna M, Banks E, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20(9):12971303.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    DePristo MA, Banks E, Poplin R, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43(5):491498.

  • 28

    Cingolani P, Platts A, Wang LL, et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin). 2012;6(2):8092.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Adzhubei IA, Schmidt S, Peshkin L, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248249.

  • 30

    Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214218.

  • 31

    Cho A, Shim JE, Kim E, et al. MUFFINN: cancer gene discovery via network analysis of somatic mutation data. Genome Biol. 2016;17(1):129.

  • 32

    Ramos AH, Lichtenstein L, Gupta M, et al. Oncotator: cancer variant annotation tool. Hum Mutat. 2015;36(4):E2423E2429.

  • 33

    Wang Q, Shashikant CS, Jensen M, et al. Novel metrics to measure coverage in whole exome sequencing datasets reveal local and global non-uniformity. Sci Rep. 2017;7(1):885.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Monticone M, Biollo E, Maffei M, et al. Gene expression deregulation by KRAS G12D and G12V in a BRAF V600E context. Mol Cancer. 2008;7:92.

  • 35

    Stolze B, Reinhart S, Bulllinger L, et al. Comparative analysis of KRAS codon 12, 13, 18, 61, and 117 mutations using human MCF10A isogenic cell lines. Sci Rep. 2015;5:8535.

  • 36

    Braicu C, Buse M, Busuioc C, et al. A comprehensive review on MAPK: a promising therapeutic target in cancer. Cancers (Basel). 2019;11(10):E1618.

  • 37

    Anglesio MS, Papadopoulos N, Ayhan A, et al. Cancer-associated mutations in endometriosis without cancer. N Engl J Med. 2017;376(19):18351848.

  • 38

    Zhang Y, Ingram DA, Murphy MP, et al. Release of proinflammatory mediators and expression of proinflammatory adhesion molecules by endothelial progenitor cells. Am J Physiol Heart Circ Physiol. 2009;296(5):H1675H1682.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Chen W, Guo Y, Walker EJ, et al. Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain. Arterioscler Thromb Vasc Biol. 2013;33(2):305310.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Winkler EA, Bell RD, Zlokovic BV. Pericyte-specific expression of PDGF beta receptor in mouse models with normal and deficient PDGF beta receptor signaling. Mol Neurodegener. 2010;5:32.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Karasozen Y, Osbun JW, Parada CA, et al. Somatic PDGFRB activating variants in fusiform cerebral aneurysms. Am J Hum Genet. 2019;104(5):968976.

  • 42

    Song Q, Yi F, Zhang Y, et al. CRKL regulates alternative splicing of cancer-related genes in cervical cancer samples and HeLa cell. BMC Cancer. 2019;19(1):499.

  • 43

    Cheung HW, Du J, Boehm JS, et al. Amplification of CRKL induces transformation and epidermal growth factor receptor inhibitor resistance in human non-small cell lung cancers. Cancer Discov. 2011;1(7):608625.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Lin F, Chengyao X, Qingchang L, et al. CRKL promotes lung cancer cell invasion through ERK-MMP9 pathway. Mol Carcinog. 2015;54(suppl 1):E35E44.

  • 45

    Sun Z, Lawson DA, Sinclair E, et al. Endovascular biopsy: strategy for analyzing gene expression profiles of individual endothelial cells obtained from human vessels. Biotechnol Rep (Amst). 2015;7:157165.

    • Crossref
    • Search Google Scholar
    • Export Citation

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