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Hum Mol Genet. 2015 Dec 1;24(23):6687-98. doi: 10.1093/hmg/ddv373. Epub 2015 Sep 11.

Molecular analyses of juvenile granulosa cell tumors bearing AKT1 mutations provide insights into tumor biology and therapeutic leads.

Author information

1
Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France, Faculty of Biological Sciences, Université Paris Diderot-Paris VII, 75205 Paris, France.
2
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.
3
Hôpital Necker-Enfants Malades, Paris, France, Faculty of Medicine, Université Paris Descartes-Paris V, 75015 Paris, France.
4
Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
5
GenoSplice, Ltd, Paris, France.
6
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.

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.

PMID:
26362254
DOI:
10.1093/hmg/ddv373
[Indexed for MEDLINE]

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