期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 127, 期 6, 页码 2310-2325出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI91291
关键词
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资金
- FWO [G.0689.12N, G.0791.14]
- Interuniversitaire Attractiepolen (IUAP)
- Special Research Fund (BOF) KU Leuven [PF/10/016]
- Foundation Against Cancer [2014-126, 2012-F2]
- Fondation ARC [PJA2013120021]
- La Ligue Contre le Cancer (Equipe Labelisee)
- Fund for Scientific Research Flanders (FWO)
- VIB PhD international program
- Marie-Curie/VIB OMICs program
- French Ministry of Research
- Fondation pour la Recherche Medicale [FDT20150532362]
- Melanoma Research Alliance (Team Science Research Award
- USA)
- Kom op tegen Kanker
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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