title: GNA14 Somatic Mutation Causes Congenital and Sporadic Vascular Tumors by MAPK Activation.
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.
authors.affiliation: Department 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.
authors.forename: Young H
authors.initials: YH
authors.lastname: Lim
authors.affiliation: Department of Dermatology, School of Medicine, Yale University, New Haven, CT 06510, USA.
authors.forename: Antonella
authors.initials: A
authors.lastname: Bacchiocchi
authors.affiliation: Department of Genetics, School of Medicine, Yale University, New Haven, CT 06510, USA.
authors.forename: Jingyao
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Department of Dermatology, School of Medicine, Yale University, New Haven, CT 06510, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Straub
authors.affiliation: Departments of Dermatology and Pediatrics, School of Medicine, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Bruckner
authors.affiliation: Department of Dermatology, Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.
authors.forename: Lionel
authors.initials: L
authors.lastname: Bercovitch
authors.affiliation: Section of Plastic Surgery, Department of Surgery, School of Medicine, Yale University, New Haven, CT 06510, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Narayan
authors.affiliation: Department 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.
authors.forename: Jennifer
authors.initials: J
authors.lastname: McNiff
authors.affiliation: Department 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.
authors.forename: Christine
authors.initials: C
authors.lastname: Ko
authors.affiliation: Department of Dermatology, Warren Alpert Medical School, Brown University, Providence, RI 02903, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Robinson-Bostom
authors.affiliation: Department 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.
authors.forename: Richard
authors.initials: R
authors.lastname: Antaya
authors.affiliation: Department of Dermatology, School of Medicine, Yale University, New Haven, CT 06510, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Halaban
authors.affiliation: Department 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.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Choate
mesh_terms: D002478:Cells, Cultured; D002675:Child, Preschool; D004789:Enzyme Activation; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019043:Vascular Neoplasms / Q000151:congenital* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
chemical_list: C554062:GNA11 protein, human; D044385:GTP-Binding Protein alpha Subunits; D036341:Intercellular Signaling Peptides and Proteins; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; C119109:GNA14 protein, human; D043802:GTP-Binding Protein alpha Subunits, Gq-G11