Kinase fusions are frequent in Spitz tumours and spitzoid melanomas.
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.
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 415 E 68th Street, New York, New York 10065, USA.|Department of Dermatology and Venereology, Medical University of Graz, Auenbruggerplatz 8, 8036 Graz, Austria.
Thomas
T
Wiesner
Foundation Medicine, 1 Kendall Sq B6501, Cambridge, Massachusetts 02139, USA.
Jie
J
He
Foundation Medicine, 1 Kendall Sq B6501, Cambridge, Massachusetts 02139, USA.
Roman
R
Yelensky
Departments of Dermatology and Pathology, UCSF Cardiovascular Research Institute, 555 Mission Bay Blvd. South, Room 252K, Box 3118, San Francisco, California 94158-9001, USA.
Rosaura
R
Esteve-Puig
Departments of Dermatology and Pathology, UCSF Cardiovascular Research Institute, 555 Mission Bay Blvd. South, Room 252K, Box 3118, San Francisco, California 94158-9001, USA.
Thomas
T
Botton
Departments of Dermatology and Pathology, UCSF Cardiovascular Research Institute, 555 Mission Bay Blvd. South, Room 252K, Box 3118, San Francisco, California 94158-9001, USA.
Iwei
I
Yeh
Foundation Medicine, 1 Kendall Sq B6501, Cambridge, Massachusetts 02139, USA.
Doron
D
Lipson
Foundation Medicine, 1 Kendall Sq B6501, Cambridge, Massachusetts 02139, USA.
Geoff
G
Otto
Foundation Medicine, 1 Kendall Sq B6501, Cambridge, Massachusetts 02139, USA.
Kristina
K
Brennan
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 415 E 68th Street, New York, New York 10065, USA.|Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue New York, New York 10065, USA.
Rajmohan
R
Murali
Departments of Dermatology and Pathology, UCSF Cardiovascular Research Institute, 555 Mission Bay Blvd. South, Room 252K, Box 3118, San Francisco, California 94158-9001, USA.
Maria
M
Garrido
Foundation Medicine, 1 Kendall Sq B6501, Cambridge, Massachusetts 02139, USA.
Vincent A
VA
Miller
Foundation Medicine, 1 Kendall Sq B6501, Cambridge, Massachusetts 02139, USA.
Jeffrey S
JS
Ross
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 415 E 68th Street, New York, New York 10065, USA.
Michael F
MF
Berger
Departments of Dermatology and Pathology, UCSF Cardiovascular Research Institute, 555 Mission Bay Blvd. South, Room 252K, Box 3118, San Francisco, California 94158-9001, USA.
Alyssa
A
Sparatta
Dermatopathologie Friedrichshafen, Siemensstraße 6/1, 88048 Friedrichshafen, Germany.
Gabriele
G
Palmedo
Department of Dermatology and Venereology, Medical University of Graz, Auenbruggerplatz 8, 8036 Graz, Austria.
Lorenzo
L
Cerroni
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 415 E 68th Street, New York, New York 10065, USA.
Klaus J
KJ
Busam
Dermatopathologie Friedrichshafen, Siemensstraße 6/1, 88048 Friedrichshafen, Germany.
Heinz
H
Kutzner
Foundation Medicine, 1 Kendall Sq B6501, Cambridge, Massachusetts 02139, USA.
Maureen T
MT
Cronin
Foundation Medicine, 1 Kendall Sq B6501, Cambridge, Massachusetts 02139, USA.
Philip J
PJ
Stephens
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 415 E 68th Street, New York, New York 10065, USA.|Departments of Dermatology and Pathology, UCSF Cardiovascular Research Institute, 555 Mission Bay Blvd. South, Room 252K, Box 3118, San Francisco, California 94158-9001, USA.|Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue New York, New York 10065, USA.
Boris C
BC
Bastian
D001483:Base Sequence; D004252:DNA Mutational Analysis; D015894:Genome, Human; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D008969:Molecular Sequence Data; D018332:Nevus, Epithelioid and Spindle Cell / Q000378:metabolism* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D015203:Reproducibility of Results; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D015514:Oncogene Proteins, Fusion; D011494:Protein Kinases