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Am J Hum Genet. 2016 Aug 4;99(2):443-50. doi: 10.1016/j.ajhg.2016.06.010. Epub 2016 Jul 28.

GNA14 Somatic Mutation Causes Congenital and Sporadic Vascular Tumors by MAPK Activation.

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  • 1Department of Dermatology, School of Medicine, Yale University, New Haven, CT 06510, USA; Department of Pathology, School of Medicine, Yale University, New Haven, CT 06510, USA; Department of Genetics, School of Medicine, Yale University, New Haven, CT 06510, USA.
  • 2Department of Dermatology, School of Medicine, Yale University, New Haven, CT 06510, USA.
  • 3Department of Genetics, School of Medicine, Yale University, New Haven, CT 06510, USA.
  • 4Departments of Dermatology and Pediatrics, School of Medicine, University of Colorado, Aurora, CO 80045, USA.
  • 5Department of Dermatology, Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.
  • 6Section of Plastic Surgery, Department of Surgery, School of Medicine, Yale University, New Haven, CT 06510, USA.
  • 7Department of Dermatology, School of Medicine, Yale University, New Haven, CT 06510, USA; Department of Pathology, School of Medicine, Yale University, New Haven, CT 06510, USA.
  • 8Department of Dermatology, School of Medicine, Yale University, New Haven, CT 06510, USA; Department of Pediatrics, School of Medicine, Yale University, New Haven, CT 06510, USA.
  • 9Department of Dermatology, School of Medicine, Yale University, New Haven, CT 06510, USA; Department of Pathology, School of Medicine, Yale University, New Haven, CT 06510, USA; Department of Genetics, School of Medicine, Yale University, New Haven, CT 06510, USA. Electronic address: keith.choate@yale.edu.

Abstract

Vascular tumors are among the most common neoplasms in infants and children; 5%-10% of newborns present with or develop lesions within the first 3 months of life. Most are benign infantile hemangiomas that typically regress by 5 years of age; other vascular tumors include congenital tufted angiomas (TAs), kaposiform hemangioendotheliomas (KHEs), and childhood lobular capillary hemangiomas (LCHs). Some of these lesions can become locally invasive and unresponsive to pharmacologic intervention, leading to significant complications. Recent investigation has revealed that activating mutations in HRAS, KRAS, NRAS, GNAQ, and GNA11 can cause certain types of rare childhood vascular tumors, and we have now identified causal recurrent somatic activating mutations in GNA14 by whole-exome and targeted sequencing. We found somatic activating GNA14 c.614A>T (p.Gln205Leu) mutations in one KHE, one TA, and one LCH and a GNA11 c.547C>T (p.Arg183Cys) mutation in two LCH lesions. We examined mutation pathobiology via expression of mutant GNA14 or GNA11 in primary human endothelial cells and melanocytes. GNA14 and GNA11 mutations induced changes in cellular morphology and rendered cells growth-factor independent by upregulating the MAPK pathway. Our findings identify GNA14 mutations as a cause of childhood vascular tumors, offer insight into mechanisms of oncogenic transformation by mutations affecting Gaq family members, and identify potential targets for therapeutic intervention.

PMID:
27476652
PMCID:
PMC4974082
DOI:
10.1016/j.ajhg.2016.06.010
[PubMed - in process]
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