Comparative oncogenomics identifies tyrosine kinase FES as a tumor suppressor in melanoma
Michael Olvedy, … , Paulo De Sepulveda, Jean-Christophe Marine
Michael Olvedy, … , Paulo De Sepulveda, Jean-Christophe Marine
Published May 2, 2017
Citation Information: J Clin Invest. 2017;127(6):2310-2325. https://doi.org/10.1172/JCI91291.
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Research Article Genetics Oncology

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

Abstract

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 BRAFV600E- and NRASQ61K-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 BRAFV600E-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.

Authors

Michael Olvedy, Julie C. Tisserand, Flavie Luciani, Bram Boeckx, Jasper Wouters, Sophie Lopez, Florian Rambow, Sara Aibar, Bernard Thienpont, Jasmine Barra, Corinna Köhler, Enrico Radaelli, Sophie Tartare-Deckert, Stein Aerts, Patrice Dubreuil, Joost J. van den Oord, Diether Lambrechts, Paulo De Sepulveda, Jean-Christophe Marine

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Figure 3

FES expression is regulated by promoter methylation in human melanomas.

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FES expression is regulated by promoter methylation in human melanomas. ...
(A) Analysis of FES expression in 474 melanoma clinical samples from the TCGA cohort. The left panel shows FES mRNA levels ordered from the highest (red) to the lowest (green). The middle panel shows DNA methylation profile obtained from 19 array probes located in the CpG sites of FES. The schematic above shows a representation of the FES locus, with UTR regions in white and exons in black. CpG positions are shown as red stripes. The right panel depicts the copy number status of the FES locus split into cases that show loss (in blue) and gain (in red) and samples in which the CNA status of FES was not assessed (in gray). (B) FES expression in short-term melanoma cultures (MM) and 3 normal melanocyte cultures (NM). Upper graph shows expression of FES mRNA levels as determined by RT-qPCR. Values are normalized to the mean RNA level of normal melanocytes, which was set to 1. Error bars show mean ± SD (n = 2). The middle panel shows Western blot analysis of FES. Actin served as a loading control. The bottom panel shows methylation profile of short-term melanoma cultures and normal melanocytes as determined by bisulfite sequencing of 20 CpG sites located at positions ranging from –72 to +115 from the FES′ TSS. BRAFV600E (B) and NRASQ61K,L,R (N) mutational status is indicated on top of the sample name. (C) Expression of FES in MM031 cell culture after treatment with demethylating agent decitabine or its vehicle. The upper panel shows FES mRNA levels assessed by qRT-PCR. Western blot analysis in the 2 lower panels shows FES protein levels. GAPDH served as a loading control.