A Model for Primary Melanoma of the CNS Implicates NRAS

Abstract

Summary :In this issue of Cancer Discovery , Pedersen and colleagues present the fi rst mouse model of primary CNS melanoma, which arises when oncogenic NRAS is expressed from the endogenous Nras promoter in melanocytes during embryogenesis. In support of this model, two pediatric cases of NRAS -mutant primary melanoma of the CNS are identifi ed. Cancer Discov; 3(4); 382-3. ©2013 AACR.See related article by Pedersen et al., p. 458 (6).Melanoma can be subdivided into categories based on body location, and some characteristic presentations are exceedingly rare. NRAS is the second most commonly mutated gene in cutaneous melanoma, the most prevalent form of the disease. After BRAF , which harbors an activating mutation in 40% to 50% of cutaneous melanomas, NRAS is mutated in approximately 20% of tumors ( 1, 2 ). Although a mouse model of melanoma driven by expression of BRAF V600E in the absence of other mutations has been developed, current NRAS-driven models rely on concomitant mutations in tumor suppressor genes ( 3-5 ). In this issue of Cancer Discovery , Pedersen and colleagues ( 6 ) show that melanocytic expression of activated NRAS results in melanoma of a quite unexpected type. Here, they present the fi rst model for pediatric primary melanoma of the central nervous system (CNS), a rare but deadly disease.Primary melanoma of the CNS originates from melanocytes of the leptomeninges. Patients can present with intracranial hypertension, neurologic defi cits, subarachnoid hemorrhage, and seizures ( 7 ). Primary melanoma of the CNS in children occurs primarily in patients with neurocutaneous melanosis (NCM), a rare nonhereditary syndrome characterized by giant or multiple congenital melanocytic nevi (CMN; ref. 7 ). Although clinical data are limited, primary melanoma of the CNS in children has a poor prognosis. One study identifi ed 5 children over the course of 13 years with primary melanoma of the leptomeninges, all of whom died within 8 months of initial presentation ( 8 ). By expressing oncogenic NRAS in mouse melanocytes during embryonic development, Pedersen and colleagues ( 6 ) were able to recapitulate the pathology of CNS melanoma, with particular relevance to pediatric cases.To develop an NRAS-driven model of melanoma, Pedersen and colleagues ( 6 ) expressed NRAS G12D at physiologic levels in a spatially and temporally controlled manner. They did this by inserting a loxP -STOP-loxP cassette followed by NRAS G12D ( Nras LSL-G12D ) into the endogenous Nras locus. Tamoxifenactivated Cre recombinase, expressed in melanocytes using the tyrosinase promoter, allowed for stop codon excision and expression of NRAS G12D at 2 months of age by painting the backs of mice with tamoxifen. For expression during embryogenesis, the authors used unmodifi ed Cre recombinase.Surprisingly, expression of NRAS G12D during embryogenesis resulted in primary melanoma of the CNS, manifesting in neurologic symptoms such as hyperreactivity and motor dysfunction at a median of 4 months of age in Nras LSL-G12D homozygous mice and 12.5...

Current State of Animal (Mouse) Modeling in Melanoma Research

“…Although NRAS is rarely involved in primary melanoma of CNS, it is suggested that this model could represent some of the rare cases. 101 …”

“…Although NRAS is rarely involved in primary melanoma of CNS, it is suggested that this model could represent some of the rare cases. 101 PTEN/BRAF models. Identification of the PTEN deletion and BRAF mutations were two of the greatest discoveries in melanoma field.…”

Melanoma maligno primario del sistema nervioso central: un reto diagnóstico

“…3) Teoría neurogénica: las células pigmentadas se derivan de la cresta neural y pueden originar tumores 3 . También se han reportado anormalidades cromosómicas, como la deleción o rotura en el brazo largo y corto del cromosoma 6, con una posible pérdida en la función de genes supresores tumorales en el melanoma maligno primario del sistema nervioso central 15 , y se han diseñado modelos experimentales en ratones que demuestran la función de oncogenes 16,17 y la aparición de melanoma maligno primario del sistema nervioso central en ratones cuando el oncogén NRAS es expresado en melanocitos durante la embriogénesis por medio de un promotor NRAS endógeno 18 . Se sabe que este oncogén induce proliferación de melanocitos y lesiones melanocíticas congénitas en humanos.…”