Kinase fusions are frequent in Spitz tumours and spitzoid melanomas

Thomas Wiesner, Jie He, Roman Yelensky, Rosaura Esteve-Puig, Thomas Botton, Iwei Yeh, Doron Lipson, Geoff Otto, Kristina Brennan, Rajmohan Murali, Maria Garrido, Vincent A. Miller, Jeffrey S. Ross, Michael F. Berger, Alyssa Sparatta, Gabriele Palmedo, Lorenzo Cerroni, Klaus J. Busam, Heinz Kutzner, Maureen T. Cronin, Philip J. Stephens () and Boris C. Bastian ()
Additional contact information
Thomas Wiesner: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center
Jie He: Foundation Medicine
Roman Yelensky: Foundation Medicine
Rosaura Esteve-Puig: UCSF Cardiovascular Research Institute
Thomas Botton: UCSF Cardiovascular Research Institute
Iwei Yeh: UCSF Cardiovascular Research Institute
Doron Lipson: Foundation Medicine
Geoff Otto: Foundation Medicine
Kristina Brennan: Foundation Medicine
Rajmohan Murali: Memorial Sloan-Kettering Cancer Center
Maria Garrido: UCSF Cardiovascular Research Institute
Vincent A. Miller: Foundation Medicine
Jeffrey S. Ross: Foundation Medicine
Michael F. Berger: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center
Alyssa Sparatta: UCSF Cardiovascular Research Institute
Gabriele Palmedo: Dermatopathologie Friedrichshafen
Lorenzo Cerroni: Medical University of Graz
Klaus J. Busam: Memorial Sloan-Kettering Cancer Center
Heinz Kutzner: Dermatopathologie Friedrichshafen
Maureen T. Cronin: Foundation Medicine
Philip J. Stephens: Foundation Medicine
Boris C. Bastian: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center

Nature Communications, 2014, vol. 5, issue 1, 1-9

Abstract: Abstract Spitzoid neoplasms are a group of melanocytic tumours with distinctive histopathological features. They include benign tumours (Spitz naevi), malignant tumours (spitzoid melanomas) and tumours with borderline histopathological features and uncertain clinical outcome (atypical Spitz tumours). Their genetic underpinnings are poorly understood, and alterations in common melanoma-associated oncogenes are typically absent. Here we show that spitzoid neoplasms harbour kinase fusions of ROS1 (17%), NTRK1 (16%), ALK (10%), BRAF (5%) and RET (3%) in a mutually exclusive pattern. The chimeric proteins are constitutively active, stimulate oncogenic signalling pathways, are tumourigenic and are found in the entire biologic spectrum of spitzoid neoplasms, including 55% of Spitz naevi, 56% of atypical Spitz tumours and 39% of spitzoid melanomas. Kinase inhibitors suppress the oncogenic signalling of the fusion proteins in vitro. In summary, kinase fusions account for the majority of oncogenic aberrations in spitzoid neoplasms and may serve as therapeutic targets for metastatic spitzoid melanomas.

Date: 2014
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DOI: 10.1038/ncomms4116

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