title: PIK3CA activating mutations in facial infiltrating lipomatosis.
abstract: BACKGROUND
  Facial infiltrating lipomatosis is a nonheritable disorder characterized by hemifacial soft-tissue and skeletal overgrowth, precocious dental development, macrodontia, hemimacroglossia, and mucosal neuromas. The authors tested the hypothesis that this condition is caused by a somatic mutation in the phosphatidylinositide-3 kinase (PI3K) signaling pathway, which has been indicted in other anomalies with overgrowth.
  
  
  METHODS
  The authors extracted DNA from abnormal tissue in six individuals, generated sequencing libraries, enriched the libraries for 26 genes involved in the PI3K pathway, and designed and applied a sequential filtering strategy to analyze the sequence data for mosaic mutations.
  
  
  RESULTS
  Unfiltered sequence data contained variant reads affecting ~12 percent of basepairs in the targeted genes. Filtering reduced the fraction of targeted basepairs containing variant reads to ~0.008 percent, allowing the authors to identify causal missense mutations in PIK3CA (p.E453K, p.E542K, p.H1047R, or p.H1047L) in each affected tissue sample.
  
  
  CONCLUSIONS
  Affected tissue from individuals with facial infiltrating lipomatosis contains PIK3CA mutations that have previously been reported in cancers and in affected tissue from other nonheritable, overgrowth disorders, including congenital lipomatous overgrowth, vascular, epidermal, and skeletal anomalies syndrome, Klippel-Trenaunay syndrome, hemimegalencephaly, fibroadipose overgrowth, and macrodactyly. Because PIK3CA encodes a catalytic subunit of PI3K, and in vitro studies have shown that the overgrowth-associated mutations increase this enzyme's activity, PI3K inhibitors currently in clinical trials for patients with cancer may have a therapeutic role in patients with facial infiltrating lipomatosis. The strategy used to identify somatic mutations in patients with facial infiltrating lipomatosis is applicable to other somatic mosaic disorders that have allelic heterogeneity.
authors.affiliation: Boston, Mass. From the Departments of Plastic and Oral Surgery, Orthopaedic Surgery, and Pathology and Howard Hughes Medical Institute, Boston Children's Hospital; and the Department of Genetics, Harvard Medical School.
authors.forename: Reid A
authors.initials: RA
authors.lastname: Maclellan
authors.forename: Valerie L
authors.initials: VL
authors.lastname: Luks
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Vivero
authors.forename: John B
authors.initials: JB
authors.lastname: Mulliken
authors.forename: David
authors.initials: D
authors.lastname: Zurakowski
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Padwa
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Warman
authors.forename: Arin K
authors.initials: AK
authors.lastname: Greene
authors.forename: Kyle C
authors.initials: KC
authors.lastname: Kurek
mesh_terms: D002675:Child, Preschool; D058534:Class I Phosphatidylinositol 3-Kinases; D005145:Face / Q000473:pathology; D019066:Facies; D015723:Gene Library; D018740:Genetic Heterogeneity; D006801:Humans; D008068:Lipomatosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D009030:Mosaicism; D020125:Mutation, Missense; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D040521:Subcutaneous Tissue / Q000473:pathology
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human