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Article Dans Une Revue Journal of Clinical Investigation Année : 2017

Comparative oncogenomics identifies tyrosine kinase FES as a tumor suppressor in melanoma

Michael Olvedy
  • Fonction : Auteur
Bram Boeckx
  • Fonction : Auteur
Jasper Wouters
Sophie Lopez
  • Fonction : Auteur
Sara Aibar
Enrico Radaelli
  • Fonction : Auteur
  • PersonId : 883608

Résumé

Identification and functional validation of oncogenic drivers are essential steps toward advancing cancer precision medicine. Here, we have presented a comprehensive analysis of the somatic genomic landscape of the widely used BRAF V600E-and NRAS Q61K-driven mouse models of melanoma. By integrating the data with publically available genomic, epigenomic, and transcriptomic information from human clinical samples, we confirmed the importance of several genes and pathways previously implicated in human melanoma, including the tumor-suppressor genes phosphatase and tensin homolog (PTEN), cyclin dependent kinase inhibitor 2A (CDKN2A), LKB1, and others. Importantly, this approach also identified additional putative melanoma drivers with prognostic and therapeutic relevance. Surprisingly, one of these genes encodes the tyrosine kinase FES. Whereas FES is highly expressed in normal human melanocytes, FES expression is strongly decreased in over 30% of human melanomas. This downregulation correlates with poor overall survival. Correspondingly, engineered deletion of Fes accelerated tumor progression in a BRAF V600E-driven mouse model of melanoma. Together, these data implicate FES as a driver of melanoma progression and demonstrate the potential of cross-species oncogenomic approaches combined with mouse modeling to uncover impactful mutations and oncogenic driver alleles with clinical importance in the treatment of human cancer.
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Dates et versions

hal-01788013 , version 1 (08-05-2018)

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Michael Olvedy, Julie C Tisserand, Flavie Luciani, Bram Boeckx, Jasper Wouters, et al.. Comparative oncogenomics identifies tyrosine kinase FES as a tumor suppressor in melanoma. Journal of Clinical Investigation, 2017, 127 (6), pp.2310 - 2325. ⟨10.1172/JCI91291⟩. ⟨hal-01788013⟩
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