title: Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma.
abstract: Congenital hemangioma is a rare vascular tumor that forms in utero. Postnatally, the tumor either involutes quickly (i.e., rapidly involuting congenital hemangioma [RICH]) or partially regresses and stabilizes (i.e., non-involuting congenital hemangioma [NICH]). We hypothesized that congenital hemangiomas arise due to somatic mutation and performed massively parallel mRNA sequencing on affected tissue from eight participants. We identified mutually exclusive, mosaic missense mutations that alter glutamine at amino acid 209 (Glu209) in GNAQ or GNA11 in all tested samples, at variant allele frequencies (VAF) ranging from 3% to 33%. We verified the presence of the mutations in genomic DNA using a combination of molecular inversion probe sequencing (MIP-seq) and digital droplet PCR (ddPCR). The Glu209 GNAQ and GNA11 missense variants we identified are common in uveal melanoma and have been shown to constitutively activate MAPK and/or YAP signaling. When we screened additional archival formalin-fixed paraffin-embedded (FFPE) congenital cutaneous and hepatic hemangiomas, 4/8 had GNAQ or GNA11 Glu209 variants. The same GNAQ or GNA11 mutation is found in both NICH and RICH, so other factors must account for these tumors' different postnatal behaviors.
authors.affiliation: Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ugur M
authors.initials: UM
authors.lastname: Ayturk
authors.affiliation: Department of Plastic and Oral Surgery, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Couto
authors.affiliation: Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Hann
authors.affiliation: Department of Plastic and Oral Surgery, Boston Children's Hospital, Boston, MA 02115, USA; Vascular Anomalies Center, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Mulliken
authors.affiliation: Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Kaitlin L
authors.initials: KL
authors.lastname: Williams
authors.affiliation: Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: August Yue
authors.initials: AY
authors.lastname: Huang
authors.affiliation: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Surgery, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Fishman
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Theonia K
authors.initials: TK
authors.lastname: Boyd
authors.affiliation: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Harry P W
authors.initials: HP
authors.lastname: Kozakewich
authors.affiliation: Department of Surgery, Boston Children's Hospital, Boston, MA 02115, USA; Vascular Biology Program, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Bischoff
authors.affiliation: Department of Plastic and Oral Surgery, Boston Children's Hospital, Boston, MA 02115, USA; Vascular Anomalies Center, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Arin K
authors.initials: AK
authors.lastname: Greene
authors.affiliation: Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Vascular Anomalies Center, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: matthew.warman@childrens.harvard.edu.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Warman
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics*; D005787:Gene Frequency; D014644:Genetic Variation; D006391:Hemangioma / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008545:Melanoma / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense; D012333:RNA, Messenger / Q000235:genetics; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D012868:Skin Abnormalities / Q000175:diagnosis / Q000235:genetics*; D014604:Uveal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D000098943:Uveal Melanoma
chemical_list: C554062:GNA11 protein, human; C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; D012333:RNA, Messenger; D043802:GTP-Binding Protein alpha Subunits, Gq-G11