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Nat Commun. 2014;5:3116. doi: 10.1038/ncomms4116.

Kinase fusions are frequent in Spitz tumours and spitzoid melanomas.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 415 E 68th Street, New York, New York 10065, USA.
2
Department of Dermatology and Venereology, Medical University of Graz, Auenbruggerplatz 8, 8036 Graz, Austria.
3
Foundation Medicine, 1 Kendall Sq B6501, Cambridge, Massachusetts 02139, USA.
4
Departments of Dermatology and Pathology, UCSF Cardiovascular Research Institute, 555 Mission Bay Blvd. South, Room 252K, Box 3118, San Francisco, California 94158-9001, USA.
5
Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue New York, New York 10065, USA.
6
Dermatopathologie Friedrichshafen, Siemensstraße 6/1, 88048 Friedrichshafen, Germany.
#
Contributed equally

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.

PMID:
24445538
PMCID:
PMC4084638
DOI:
10.1038/ncomms4116
[Indexed for MEDLINE]
Free PMC Article
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