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Adult ovarian granulosa cell tumor transcriptomics: prevalence of FOXL2 target genes misregulation gives insights into the pathogenic mechanism of the p.Cys134Trp somatic mutation

Oncogene volume 32, pages 2739–2746 (2013)Cite this article

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Abstract

Ovarian granulosa cell tumors (OGCT) are the most frequent kind of sex cord-stromal tumors, and represent ∼2–5% of all ovarian malignancies. OGCTs exist as two entities, juvenile and adult types, with specific clinical and pathological characteristics. The molecular pathogenesis of these tumors has just begun to be unraveled. Indeed, recent studies have indicated that mutation and/or misregulation of the key ovarian transcription factor FOXL2 has a role in OGCT formation, although the mechanisms remain unclear. To better understand the molecular characteristics of OGCT, we studied the transcriptomic profiles of ten human adult-type OGCT samples, as well as ethnically matched granulosa cell (GC) controls. We find that the OGCT samples analyzed herein exhibit several hallmarks of cancer, including increased expression of genes linked to cell proliferation, but decreased expression of those conferring sensitivity to cell death. Moreover, genes differentially expressed in OGCTs are significantly enriched for known FOXL2 target genes, consistently with the prevalence of FOXL2 somatic mutation in these tumors. Expression of these targets is altered in a way expected to promote malignant transformation, for instance, through induction of genes associated with faster cell cycling and downregulation of genes associated with cell death. Over time, such defects may be responsible at least partly for the malignant transformation of healthy GCs into OGCT. These insights into the molecular pathogenesis of OGCTs may open the way to new efforts in the development of more targeted therapeutic strategies for OGCT patients.

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Acknowledgements

We thank Dr Ralf Bützow and Dr Unkila-Kallio for help and collection of the human OGCT samples. We thank Dr Denis Mestivier for his advice on clustering analysis of the OGCT microarray samples. BAB was funded by AMN/Université Paris Diderot-Paris 7 fellowships. MA was funded by a grant from The Helsinki University Central Hospital Research Funds. NA and MH were funded by Academy of Finland, Sigrid Juselius Foundation and Helsinki University Central Hospital. DL was funded by Université Paris Diderot-Paris 7. MBB was funded by CNRS and Université Lyon 1. RAV was funded by Institut Universitaire de France, Fondation pour la Recherche Médicale, Ligue Nationale Contre le Cancer (Comité de Paris), Groupement d'Entreprises Francaises dans la Lutte contre le Cancer, CNRS and Université Paris VII. This work was supported by grants from Fondation pour la Recherche Médicale (FRM), from The Helsinki University Central Hospital Research Funds and from Academy of Finland, Sigrid Juselius Foundation and Helsinki University Central Hospital.

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Author notes

  1. B A Benayoun

    Present address: 6Current address: Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, CA, USA,

  2. B A Benayoun and M Anttonen: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut Jacques Monod, Paris, France

    B A Benayoun, D L’Hôte & R A Veitia

  2. Université Paris Diderot/Paris, Paris, France

    B A Benayoun, D L’Hôte & R A Veitia

  3. Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland

    M Anttonen

  4. Children’s Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

    M Anttonen, N Andersson & M Heikinheimo

  5. Laboratoire de Biometrie et Biologie Evolutive, Centre National de la Recherche Scientifique, UMR 5558, Université Lyon, Villeurbanne, France

    M Bailly-Bechet

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  1. B A Benayoun
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Correspondence to R A Veitia.

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Benayoun, B., Anttonen, M., L’Hôte, D. et al. Adult ovarian granulosa cell tumor transcriptomics: prevalence of FOXL2 target genes misregulation gives insights into the pathogenic mechanism of the p.Cys134Trp somatic mutation. Oncogene 32, 2739–2746 (2013). https://doi.org/10.1038/onc.2012.298

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