title: Molecular analyses of juvenile granulosa cell tumors bearing AKT1 mutations provide insights into tumor biology and therapeutic leads.
abstract: Juvenile granulosa cell tumors (JGCTs) of the ovary are pediatric neoplasms representing 5% of all granulosa cell tumors (GCTs). Most GCTs are of adult type (AGCTs) and bear a mutation in the FOXL2 gene. The molecular basis of JGCTs is poorly understood, although mutations in the GNAS gene have been reported. We have detected in-frame duplications within the oncogene AKT1 in >60% of the JGCTs studied. Here, to evaluate the functional impact of these duplications and the existence of potential co-driver alterations, we have sequenced the transcriptome of four JGCTs and compared them with control transcriptomes. A search for gene variants detected only private alterations probably unrelated with tumorigenesis, suggesting that tandem duplications are the best candidates to underlie tumor formation in the absence of GNAS alterations. We previously showed that the duplications were specific to JGCTs. However, the screening of eight AGCTs samples without FOXL2 mutation showed the existence of an AKT1 duplication in one case, also having a stromal luteoma. The analysis of RNA-Seq data pinpointed a series of differentially expressed genes, involved in cytokine and hormone signaling and cell division-related processes. Further analyses pointed to the existence of a possible dedifferentiation process and suggested that most of the transcriptomic dysregulation might be mediated by a limited set of transcription factors perturbed by AKT1 activation. Finally, we show that commercially available AKT inhibitors can modulate the in vitro activity of various mutated forms. These results shed light on the pathogenesis of JGCTs and provide therapeutic leads for a targeted treatment.
authors.affiliation: Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France, Faculty of Biological Sciences, Université Paris Diderot-Paris VII, 75205 Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Auguste
authors.affiliation: Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France, Faculty of Biological Sciences, Université Paris Diderot-Paris VII, 75205 Paris, France.
authors.forename: Laurianne
authors.initials: L
authors.lastname: Bessière
authors.affiliation: Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France, Faculty of Biological Sciences, Université Paris Diderot-Paris VII, 75205 Paris, France, veitia.reiner@ijm.univ-paris-diderot.fr todeschini@ijm.univ-paris-diderot.fr.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Todeschini
authors.affiliation: Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France, Faculty of Biological Sciences, Université Paris Diderot-Paris VII, 75205 Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Caburet
authors.affiliation: Hôpital Necker-Enfants Malades, Paris, France, Faculty of Medicine, Université Paris Descartes-Paris V, 75015 Paris, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Sarnacki
authors.affiliation: Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Prat
authors.affiliation: Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Emanuela
authors.initials: E
authors.lastname: D'angelo
authors.affiliation: GenoSplice, Ltd, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: De La Grange
authors.affiliation: GenoSplice, Ltd, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Ariste
authors.affiliation: GenoSplice, Ltd, Paris, France.
authors.forename: Fréderic
authors.initials: F
authors.lastname: Lemoine
authors.affiliation: Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France, Faculty of Biological Sciences, Université Paris Diderot-Paris VII, 75205 Paris, France.
authors.forename: Bérangère
authors.initials: B
authors.lastname: Legois
authors.affiliation: Deparment of Pediatic Endocrinology, University Hospital of Montpellier, Montpellier, France and Deparment of Pediatic Surgery, Hôpital Lapeyronie, CHU Montpellier et Université de Montpellier, Montpellier, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Sultan
authors.affiliation: Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France, Faculty of Biological Sciences, Université Paris Diderot-Paris VII, 75205 Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Zider
authors.affiliation: Hôpital Necker-Enfants Malades, Paris, France, Faculty of Medicine, Université Paris Descartes-Paris V, 75015 Paris, France.
authors.forename: Louise
authors.initials: L
authors.lastname: Galmiche
authors.affiliation: Deparment of Pediatic Endocrinology, University Hospital of Montpellier, Montpellier, France and Deparment of Pediatic Surgery, Hôpital Lapeyronie, CHU Montpellier et Université de Montpellier, Montpellier, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Kalfa
authors.affiliation: Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France, Faculty of Biological Sciences, Université Paris Diderot-Paris VII, 75205 Paris, France, veitia.reiner@ijm.univ-paris-diderot.fr todeschini@ijm.univ-paris-diderot.fr.
authors.forename: Reiner A
authors.initials: RA
authors.lastname: Veitia
mesh_terms: D000293:Adolescent; D002455:Cell Division / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D016207:Cytokines; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006106:Granulosa Cell Tumor / Q000235:genetics* / Q000378:metabolism; D006728:Hormones; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D016207:Cytokines; D006728:Hormones; D047428:Protein Kinase Inhibitors; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt