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BRAF fusions identified in melanomas have variable treatment responses and phenotypes

Oncogene volume 38, pages 1296–1308 (2019)Cite this article

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Abstract

Oncogenic BRAF fusions have emerged as an alternate mechanism for BRAF activation in melanomas and other cancers. A number of BRAF fusions with different 5′ gene partners and BRAF exon breakpoints have been described, but the effects of different partners and breakpoints on cancer phenotypes and treatment responses has not been well characterized. Targeted RNA sequencing was used to screen 60 melanoma patient-derived xenograft (PDX) models for BRAF fusions. We identified three unique BRAF fusions, including a novel SEPT3-BRAF fusion, occurring in four tumors (4/60, 6.7%), all of which were “pan-negative” (lacking other common mutations) (4/18, 22.2%). The BRAF fusion PDX models showed variable growth rates and responses to MAPK inhibitors in vivo. Overexpression of BRAF fusions identified in our study, as well as other BRAF fusions previously identified in melanomas, resulted in a high degree of variability in 2D proliferation and 3D invasion between the different fusions. While exogenously expressed BRAF fusions all responded to MAPK inhibition in vitro, we observed potential differences in signaling and feedback mechanisms. In summary, BRAF fusions are actionable therapeutic targets, however there are significant differences in phenotypes, treatment responses, and signaling which may be clinically relevant.

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Acknowledgements

We thank the patients and their families for donating tissue to the International Melanoma Biorepository and Research Laboratory at the University of Colorado Cancer Center. We thank the Melanoma Scientific Advisory Board at the University of Colorado for their support. The work presented here was supported in part by the Amy Davis Foundation, the Moore Family Foundation, and the Heidi Horner Foundation. Additionally, funding was also provided by the Genomic and Microarray Shared Resource of Colorado’s NIH/NCI Cancer Center Support Grant P30CA046934, NIH/N CATS CCTSI Grant UL1 TR001082, and Cancer League of Colorado.

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Authors and Affiliations

  1. Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, CO, USA

    Jacqueline A. Turner, Judson G. T. Bemis, Stacey M. Bagby, Anna Capasso, Betelehem W. Yacob, Tugs-Saikhan Chimed, Robert Van Gulick, Hannah Lee, John J. Tentler, Todd Pitts, William A. Robinson & Kasey L. Couts

  2. Department of Medicine, Internal Medicine Residency Training Program, University of Colorado Denver, Aurora, CO, USA

    Hannah Lee

  3. Division Surgical Oncology, Department of Surgery, University of Colorado Denver, Aurora, CO, USA

    Richard Tobin & Martin McCarter

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  1. Jacqueline A. Turner
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Correspondence to Kasey L. Couts.

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Turner, J.A., Bemis, J.G.T., Bagby, S.M. et al. BRAF fusions identified in melanomas have variable treatment responses and phenotypes. Oncogene 38, 1296–1308 (2019). https://doi.org/10.1038/s41388-018-0514-7

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