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Recurrent BRAF kinase fusions in melanocytic tumors offer an opportunity for targeted therapy

Authors

  • Thomas Botton,

    1. Departments of Dermatology and Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
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    • These authors contributed equally to this work.
  • Iwei Yeh,

    1. Departments of Dermatology and Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
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    • These authors contributed equally to this work.
  • Tyrrell Nelson,

    1. Departments of Dermatology and Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
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  • Swapna S. Vemula,

    1. Departments of Dermatology and Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
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  • Alyssa Sparatta,

    1. Departments of Dermatology and Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
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  • Maria C. Garrido,

    1. Departments of Dermatology and Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
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  • Maryline Allegra,

    1. Inserm U1065, Centre Méditerranéen de Médecine Moléculaire, Equipe 1, Biologie et Pathologies des Mélanocytes de la Pigmentation Cutanée au Mélanome, Nice, France
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  • Stephane Rocchi,

    1. Inserm U1065, Centre Méditerranéen de Médecine Moléculaire, Equipe 1, Biologie et Pathologies des Mélanocytes de la Pigmentation Cutanée au Mélanome, Nice, France
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  • Philippe Bahadoran,

    1. Inserm U1065, Centre Méditerranéen de Médecine Moléculaire, Equipe 1, Biologie et Pathologies des Mélanocytes de la Pigmentation Cutanée au Mélanome, Nice, France
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  • Timothy H. McCalmont,

    1. Departments of Dermatology and Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
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  • Philip E. LeBoit,

    1. Departments of Dermatology and Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
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  • Elizabeth A. Burton,

    1. Plexxikon Inc., Berkeley, CA, USA
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  • Gideon Bollag,

    1. Plexxikon Inc., Berkeley, CA, USA
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  • Robert Ballotti,

    1. Inserm U1065, Centre Méditerranéen de Médecine Moléculaire, Equipe 1, Biologie et Pathologies des Mélanocytes de la Pigmentation Cutanée au Mélanome, Nice, France
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  • Boris C. Bastian

    Corresponding author
    1. Departments of Dermatology and Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
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Summary

BRAF is the most prevalent oncogene and an important therapeutic target in melanoma. In some cancers, BRAF is activated by rearrangements that fuse its kinase domain to 5′ partner genes. We examined 848 comparative genomic hybridization profiles of melanocytic tumors and found copy number transitions within BRAF in 10 tumors, of which six could be further characterized by sequencing. In all, the BRAF kinase domain was fused in-frame to six N-terminal partners. No other mutations were identified in melanoma oncogenes. One of the seven melanoma cell lines without known oncogenic mutations harbored a similar BRAF fusion, which constitutively activated the MAP kinase pathway. Sorafenib, but not vemurafenib, could block MAP kinase pathway activation and proliferation of the cell line at clinically relevant concentrations, whereas BRAFV600E mutant melanoma cell lines were significantly more sensitive to vemurafenib. The patient from whom the cell line was derived showed a durable clinical response to sorafenib.

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