Primary melanoma of the CNS in children is driven by congenital expression of oncogenic NRAS in melanocytes

Malin Pedersen; Heidi V N Küsters-Vandevelde; Amaya Viros; Patricia J T A Groenen; Berta Sanchez-Laorden; Jacobus H. Gilhuis; Ilse A C H van Engen- van Grunsven; Willy Renier; Jolanda Schieving; Ion Niculescu-Duvaz; Caroline J. Springer; Benno Küsters; Pieter Wesseling; Willeke A M Blokx; Richard Marais

doi:10.1158/2159-8290.CD-12-0464

Primary melanoma of the CNS in children is driven by congenital expression of oncogenic NRAS in melanocytes

Malin Pedersen, Heidi V N Küsters-Vandevelde, Amaya Viros, Patricia J T A Groenen, Berta Sanchez-Laorden, Jacobus H. Gilhuis, Ilse A C H van Engen- van Grunsven, Willy Renier, Jolanda Schieving, Ion Niculescu-Duvaz, Caroline J. Springer, Benno Küsters, Pieter Wesseling, Willeke A M Blokx, Richard Marais^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

UNLABELLED: NRAS mutations are common in human melanoma. To produce a mouse model of NRAS-driven melanoma, we expressed oncogenic NRAS (NRAS(G12D)) in mouse melanocytes. When NRAS(G12D) was expressed in the melanocytes of developing embryos, it induced melanocyte proliferation and congenital melanocytic lesions reminiscent of human blue nevi but did not induce cutaneous melanoma. Unexpectedly, however, it did induce early-onset primary melanoma of the central nervous system (CNS). The tumors were rapidly proliferating and caused neurologic symptoms, rapid health deterioration, and death. NRAS is not a common driver oncogene of primary melanoma of the CNS in adults, but we report two cases of primary melanoma of the CNS in children, both of which carried oncogenic mutations in NRAS. We conclude that acquisition of somatic mutations in NRAS in CNS melanocytes is a predisposing risk factor for primary melanoma of the CNS in children, and we present a mouse model of this disease.

SIGNIFICANCE: We show that the acquisition of NRAS mutations in melanocytes during embryogenesis is a risk factor for early-onset melanoma of the CNS. We have developed a powerful mouse model to study this rare but devastating childhood disease, and to develop therapeutic approaches for its treatment.

Original language	English
Pages (from-to)	458-469
Number of pages	12
Journal	Cancer Discovery
Volume	3
Issue number	4
DOIs	https://doi.org/10.1158/2159-8290.CD-12-0464
Publication status	Published - Apr 2013
Externally published	Yes

Keywords

Animals
Central Nervous System Neoplasms/genetics
Child
Child, Preschool
Female
Genes, ras/genetics
Humans
Male
Melanocytes/metabolism
Melanoma/genetics
Mice
Mice, Inbred C57BL

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10.1158/2159-8290.CD-12-0464

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Pedersen, M., Küsters-Vandevelde, H. V. N., Viros, A., Groenen, P. J. T. A., Sanchez-Laorden, B., Gilhuis, J. H., van Engen- van Grunsven, I. A. C. H., Renier, W., Schieving, J., Niculescu-Duvaz, I., Springer, C. J., Küsters, B., Wesseling, P., Blokx, W. A. M., & Marais, R. (2013). Primary melanoma of the CNS in children is driven by congenital expression of oncogenic NRAS in melanocytes. Cancer Discovery, 3(4), 458-469. https://doi.org/10.1158/2159-8290.CD-12-0464

@article{846af03237084b06910b25e3d6f78ad1,

title = "Primary melanoma of the CNS in children is driven by congenital expression of oncogenic NRAS in melanocytes",

abstract = "UNLABELLED: NRAS mutations are common in human melanoma. To produce a mouse model of NRAS-driven melanoma, we expressed oncogenic NRAS (NRAS(G12D)) in mouse melanocytes. When NRAS(G12D) was expressed in the melanocytes of developing embryos, it induced melanocyte proliferation and congenital melanocytic lesions reminiscent of human blue nevi but did not induce cutaneous melanoma. Unexpectedly, however, it did induce early-onset primary melanoma of the central nervous system (CNS). The tumors were rapidly proliferating and caused neurologic symptoms, rapid health deterioration, and death. NRAS is not a common driver oncogene of primary melanoma of the CNS in adults, but we report two cases of primary melanoma of the CNS in children, both of which carried oncogenic mutations in NRAS. We conclude that acquisition of somatic mutations in NRAS in CNS melanocytes is a predisposing risk factor for primary melanoma of the CNS in children, and we present a mouse model of this disease.SIGNIFICANCE: We show that the acquisition of NRAS mutations in melanocytes during embryogenesis is a risk factor for early-onset melanoma of the CNS. We have developed a powerful mouse model to study this rare but devastating childhood disease, and to develop therapeutic approaches for its treatment.",

keywords = "Animals, Central Nervous System Neoplasms/genetics, Child, Child, Preschool, Female, Genes, ras/genetics, Humans, Male, Melanocytes/metabolism, Melanoma/genetics, Mice, Mice, Inbred C57BL",

author = "Malin Pedersen and K{\"u}sters-Vandevelde, {Heidi V N} and Amaya Viros and Groenen, {Patricia J T A} and Berta Sanchez-Laorden and Gilhuis, {Jacobus H.} and {van Engen- van Grunsven}, {Ilse A C H} and Willy Renier and Jolanda Schieving and Ion Niculescu-Duvaz and Springer, {Caroline J.} and Benno K{\"u}sters and Pieter Wesseling and Blokx, {Willeke A M} and Richard Marais",

note = "{\textcopyright}2013 AACR.",

year = "2013",

month = apr,

doi = "10.1158/2159-8290.CD-12-0464",

language = "English",

volume = "3",

pages = "458--469",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "4",

}

Pedersen, M, Küsters-Vandevelde, HVN, Viros, A, Groenen, PJTA, Sanchez-Laorden, B, Gilhuis, JH, van Engen- van Grunsven, IACH, Renier, W, Schieving, J, Niculescu-Duvaz, I, Springer, CJ, Küsters, B, Wesseling, P, Blokx, WAM & Marais, R 2013, 'Primary melanoma of the CNS in children is driven by congenital expression of oncogenic NRAS in melanocytes', Cancer Discovery, vol. 3, no. 4, pp. 458-469. https://doi.org/10.1158/2159-8290.CD-12-0464

TY - JOUR

T1 - Primary melanoma of the CNS in children is driven by congenital expression of oncogenic NRAS in melanocytes

AU - Pedersen, Malin

AU - Küsters-Vandevelde, Heidi V N

AU - Viros, Amaya

AU - Groenen, Patricia J T A

AU - Sanchez-Laorden, Berta

AU - Gilhuis, Jacobus H.

AU - van Engen- van Grunsven, Ilse A C H

AU - Renier, Willy

AU - Schieving, Jolanda

AU - Niculescu-Duvaz, Ion

AU - Springer, Caroline J.

AU - Küsters, Benno

AU - Wesseling, Pieter

AU - Blokx, Willeke A M

AU - Marais, Richard

PY - 2013/4

Y1 - 2013/4

N2 - UNLABELLED: NRAS mutations are common in human melanoma. To produce a mouse model of NRAS-driven melanoma, we expressed oncogenic NRAS (NRAS(G12D)) in mouse melanocytes. When NRAS(G12D) was expressed in the melanocytes of developing embryos, it induced melanocyte proliferation and congenital melanocytic lesions reminiscent of human blue nevi but did not induce cutaneous melanoma. Unexpectedly, however, it did induce early-onset primary melanoma of the central nervous system (CNS). The tumors were rapidly proliferating and caused neurologic symptoms, rapid health deterioration, and death. NRAS is not a common driver oncogene of primary melanoma of the CNS in adults, but we report two cases of primary melanoma of the CNS in children, both of which carried oncogenic mutations in NRAS. We conclude that acquisition of somatic mutations in NRAS in CNS melanocytes is a predisposing risk factor for primary melanoma of the CNS in children, and we present a mouse model of this disease.SIGNIFICANCE: We show that the acquisition of NRAS mutations in melanocytes during embryogenesis is a risk factor for early-onset melanoma of the CNS. We have developed a powerful mouse model to study this rare but devastating childhood disease, and to develop therapeutic approaches for its treatment.

AB - UNLABELLED: NRAS mutations are common in human melanoma. To produce a mouse model of NRAS-driven melanoma, we expressed oncogenic NRAS (NRAS(G12D)) in mouse melanocytes. When NRAS(G12D) was expressed in the melanocytes of developing embryos, it induced melanocyte proliferation and congenital melanocytic lesions reminiscent of human blue nevi but did not induce cutaneous melanoma. Unexpectedly, however, it did induce early-onset primary melanoma of the central nervous system (CNS). The tumors were rapidly proliferating and caused neurologic symptoms, rapid health deterioration, and death. NRAS is not a common driver oncogene of primary melanoma of the CNS in adults, but we report two cases of primary melanoma of the CNS in children, both of which carried oncogenic mutations in NRAS. We conclude that acquisition of somatic mutations in NRAS in CNS melanocytes is a predisposing risk factor for primary melanoma of the CNS in children, and we present a mouse model of this disease.SIGNIFICANCE: We show that the acquisition of NRAS mutations in melanocytes during embryogenesis is a risk factor for early-onset melanoma of the CNS. We have developed a powerful mouse model to study this rare but devastating childhood disease, and to develop therapeutic approaches for its treatment.

KW - Animals

KW - Central Nervous System Neoplasms/genetics

KW - Child

KW - Child, Preschool

KW - Female

KW - Genes, ras/genetics

KW - Humans

KW - Male

KW - Melanocytes/metabolism

KW - Melanoma/genetics

KW - Mice

KW - Mice, Inbred C57BL

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U2 - 10.1158/2159-8290.CD-12-0464

DO - 10.1158/2159-8290.CD-12-0464

M3 - Article

C2 - 23303902

AN - SCOPUS:84877680589

SN - 2159-8274

VL - 3

SP - 458

EP - 469

JO - Cancer Discovery

JF - Cancer Discovery

IS - 4

ER -

Primary melanoma of the CNS in children is driven by congenital expression of oncogenic NRAS in melanocytes

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