title: A Hot-spot of In-frame Duplications Activates the Oncoprotein AKT1 in Juvenile Granulosa Cell Tumors.
abstract: BACKGROUND
  Ovarian granulosa cell tumors are the most common sex-cord stromal tumors and have juvenile (JGCTs) and adult forms. In a previous study we reported the occurrence of activating somatic mutations of Gαs, which transduces mitogenic signals, in 30% of the analyzed JGCTs.
  
  
  METHODS
  We have searched for alterations in other proteins involved in ovarian mitogenic signaling. We focused on the PI3K-AKT axis. As we found mutations in AKT1, we analyzed the subcellular localization of the mutated proteins and performed functional explorations using Western-blot and luciferase assays.
  
  
  RESULTS
  We detected in-frame duplications affecting the pleckstrin-homology domain of AKT1 in more than 60% of the tumors occurring in girls under 15 years of age. The somatic status of the mutations was confirmed when peritumoral DNA was available. The JGCTs without duplications carried point mutations affecting highly conserved residues. Several of these substitutions were somatic lesions. The mutated proteins carrying the duplications had a non-wild-type subcellular distribution, with a marked enrichment at the plasma membrane. This led to a striking degree of AKT1 activation demonstrated by a strong phosphorylation level and by reporter assays.
  
  
  CONCLUSIONS
  Our study incriminates somatic mutations of AKT1 as a major event in the pathogenesis of JGCTs. The existence of AKT inhibitors currently tested in clinical trials opens new perspectives for targeted therapies for these tumors, which are currently treated with standard non-specific chemotherapy protocols.
authors.affiliation: Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France ; Université Paris Diderot-Paris VII, 75205 Paris Cedex 13, France.
authors.forename: Laurianne
authors.initials: L
authors.lastname: Bessière
authors.affiliation: Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France ; Université Paris Diderot-Paris VII, 75205 Paris Cedex 13, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Todeschini
authors.affiliation: Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France ; Université Paris Diderot-Paris VII, 75205 Paris Cedex 13, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Auguste
authors.affiliation: Hôpital Necker Enfants-Malades, Paris, France ; Université Paris Descartes-Paris V, 75015 Paris, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Sarnacki
authors.affiliation: Université Paris Diderot-Paris VII, 75205 Paris Cedex 13, France ; Molecules Thérapeutiques in silico, Université Paris Diderot, INSERM UMR973, Paris 75013, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Flatters
authors.affiliation: Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France ; Université Paris Diderot-Paris VII, 75205 Paris Cedex 13, France.
authors.forename: Bérangère
authors.initials: B
authors.lastname: Legois
authors.affiliation: Deparment of Pediatric Endocrinology, University Hospital of Montpellier, Montpellier, France ; Deparment of Pediatric Surgery, Hôpital Lapeyronie, CHU Montpellier, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Sultan
authors.affiliation: Deparment of Pediatric Endocrinology, University Hospital of Montpellier, Montpellier, France ; Deparment of Pediatric Surgery, Hôpital Lapeyronie, CHU Montpellier, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Kalfa
authors.affiliation: Hôpital Necker Enfants-Malades, Paris, France ; Université Paris Descartes-Paris V, 75015 Paris, France.
authors.forename: Louise
authors.initials: L
authors.lastname: Galmiche
authors.affiliation: Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France ; Université Paris Diderot-Paris VII, 75205 Paris Cedex 13, France.
authors.forename: Reiner A
authors.initials: RA
authors.lastname: Veitia
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D020440:Gene Duplication / Q000235:genetics*; D006106:Granulosa Cell Tumor / Q000201:enzymology* / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D010766:Phosphorylation; D017354:Point Mutation / Q000235:genetics; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016364:Reading Frames / Q000235:genetics*; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT1; Activating mutation; Juvenile granulosa cell tumor; Oncogene; Oncoprotein; Ovary