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• W2033512653 abstract "Linking phenotypic patterns of melanocytic neoplasia to specific gene mutations allows more precise predicting of clinical behavior and response to targeted therapy. In this issue, Kinsler et al. provide evidence that multiple congenital nevi with central nervous system lesions are likely exclusively the result of mosaic mutations in NRAS. We discuss the link between mosaic NRAS mutations, cellular senescence, and clinical phenotype in these nevi. Linking phenotypic patterns of melanocytic neoplasia to specific gene mutations allows more precise predicting of clinical behavior and response to targeted therapy. In this issue, Kinsler et al. provide evidence that multiple congenital nevi with central nervous system lesions are likely exclusively the result of mosaic mutations in NRAS. We discuss the link between mosaic NRAS mutations, cellular senescence, and clinical phenotype in these nevi. Activation of specific signaling pathways through postzygotic gene mutation (mosaicism) has been shown to be responsible for the development of both benign and malignant tumors of skin. Commonly, these mutations constitutively activate an isoform of the RAS family of GTPase proteins, HRAS, NRAS, or KRAS, and involve hot spot mutations at codons 12, 13, and 61. These RAS proteins have GTP/GDP binding and GTPase activity, allowing them to function as binary switches for pathway activation, leading to increased cell proliferation. Congenital melanocytic nevi (CMNs) are benign clonal proliferations of cells of neural crest origin that occur overall in ∼1% of infants. CMNs have been classified based on size as small (<1.5cm in diameter in the adult), medium sized (1.5–20cm), large (>20cm), and sometimes giant (>40cm) (Alikhan et al., 2012Alikhan A. Ibrahimi O.A. Eisen D.B. Congenital melanocytic nevi: where are we now? Part I. Clinical presentation, epidemiology, pathogenesis, histology, malignant transformation, and neurocutaneous melanosis.J Am Acad Dermatol. 2012; 67: 495-517Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar. In contrast to the common occurrence of small CMNs, larger CMNs have an estimated incidence of 1 in 20,000 individuals. Neuromelanosis of the meninges and brain parenchyma (neurocutaneous melanosis (NCM)) may be associated with CMNs, particularly in large CMNs with ≥3 (multiple) satellite nevi; whether there is a greater risk of neuromelanosis with truncal large CMNs has been controversial. Symptomatic NCM has a poor prognosis because of functional impairment and a high rate of transformation of central nervous system melanocytic lesions to melanoma, with more than half of affected patients dying within 3 years of diagnosis. NCM can be detected by T1-weighted magnetic resonance imaging (MRI) images, but the absence of neuromelanosis by MRI does not rule out its presence and finding neuromelanosis does not predict its course. NCM-associated signs tend to manifest by 2 to 3 years of age, but a subset of patients present later in childhood. These signs can include hydrocephalus, seizures, evidence of increased intracranial pressure (headache, vomiting, lethargy), developmental delay, hypotonia, neurogenic bowel and bladder dysfunction, sensorimotor defects, and cranial nerve palsies. The percentage of patients with large CMNs who develop neuromelanosis (2.5–45%) and with NCM who become symptomatic (4–68%) varies greatly, probably reflecting the small size of most studies and specialty of the authors. In a survey of 599 individuals with large or giant truncal CMNs through the Nevus Network, a patient support group, 7.5% had NCM based on MRI and/or symptoms, and 4.8% had symptomatic NCM. Multiple satellite nevi were noted in at least 87% of individuals with NCM, and 34% with symptomatic NCMs died (Bett, 2006Bett B.J. Large or multiple congenital melanocytic nevi: occurrence of neurocutaneous melanocytosis in 1008 persons.J Am Acad Dermatol. 2006; 54: 767-777Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). In common acquired pigmented nevi, small CMNs, and in 50–60% of melanomas, hot spot V600E mutations in BRAF, encoding a signaling molecule downstream of RAS, predominate. The HRAS isoform of the RAS gene is mutated in ∼12% of Spitz nevi, but is infrequently mutated in conventional nevi or melanomas. On the other hand, the majority of giant, large, and medium-sized CMNs, as well as 20% of acquired pigmented nevi and 15–20% of melanomas, result from NRAS activating mutations. Mutations in BRAF and NRAS are almost invariably mutually exclusive, suggesting that they may function on the same RAS/extracellular signal–regulated kinase (ERK) signaling pathway (Figure 1). One question that has not been addressed previously is whether CMNs at multiple body sites, often as satellites to a giant CMN, are clonal or arise de novo as different mutations in neuroectodermal cells. In addition, the underlying mutations in neuromelanosis and their relation to coexistent CMNs have not been explored. In this issue, Kinsler et al., 2013Kinsler V.A. Thomas A.C. Ishida M. et al.Multiple congenital melanocytic naevi and neurocutaneous melanosis are caused by post-zygotic mutations in codon 61 of NRAS.J Invest Dermatol. 2013; 132: 2229-2236Abstract Full Text Full Text PDF Scopus (211) Google Scholar evaluated lesional samples of congenital nevi and associated abnormal nervous system tissue and/or melanomas from 15 patients with at least 3 congenital nevi. All but one had a medium-size to giant CMN, and most had at least 50 satellite lesions. Of the 15 patients, 12 showed an NRAS mutation at codon 61 (Q61K more often than Q61R) within the tissue samples from the large CMN and in at least one additional congenital nevus, if available. All 11 melanocytic and nonmelanocytic neurologic lesions from 5 of these patients also had matching NRAS codon 61 mutations. None of the blood samples or clinically unaffected tissue samples carried this mutation, providing evidence that postzygotic mutations in NRAS involving the skin and central nervous system underlie the development of multiple CMNs or large CMNs in association with neuroectodermal abnormalities, particularly leptomeningeal melanosis. The underlying mechanism for the neurocutaneous patterning of mosaicism in melanocyte genes has been poorly understood. Keratinocyte gene mosaicism, as occurs in epidermal nevi and nevus sebaceus, is expressed phenotypically along lines of Blaschko, the lines of embryologic development of skin. In contrast, small- to medium-sized congenital (and acquired) pigmented nevi are round to oval and large and giant CMNs tend to be garment-like, resembling a bathing suit, shirt, or cuff (Torrelo et al., 2005Torrelo A. Baselga E. Nagore E. et al.Delineation of the various shapes and patterns of nevi.Eur J Dermatol. 2005; 15: 439-450PubMed Google Scholar). These pattern differences likely reflect the different migratory patterns of cells during embryogenesis (i.e., keratinocyte vs. melanocyte), and they may depend on the timing of mutation occurrence during embryogenesis and the effect of the underlying gene mutation on cell proliferation, migration, and survival. Kinsler et al., 2013Kinsler V.A. Thomas A.C. Ishida M. et al.Multiple congenital melanocytic naevi and neurocutaneous melanosis are caused by post-zygotic mutations in codon 61 of NRAS.J Invest Dermatol. 2013; 132: 2229-2236Abstract Full Text Full Text PDF Scopus (211) Google Scholar provide evidence that multiple nevus sites and associated neurologic lesions show the same mutation, confirming the clonality of these lesions. Theoretically, a mutation that occurs early in neuroectodermal embryogenesis would lead to lesions with the same mutation at more than one site (i.e., leptomeningeal and skin lesions), as well as to larger and greater numbers of cutaneous nevi that harbor the same mutation. The phenotypic characteristics of nevi with NRAS Q61 mutations (larger CMNs, often multiple) versus BRAF V600 mutations (smaller CMNs) likely also reflect the function of NRAS versus BRAF gene products. Activated NRAS leads to signaling through both ERK and the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, in contrast to activation of only ERK signaling with activated BRAF. In addition to increasing cell proliferation, PI3K/AKT activation promotes melanocyte survival and directional migration through Rac1 stimulation (Li et al., 2012Li A. Ma Y. Jin M. Activated mutant NRas(Q61K) drives aberrant melanocyte signaling, survival, and invasiveness via a Rac1-dependent mechanism.J Invest Dermatol. 2012; 132: 2610-2621Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar; the ability of NRAS mutations to stimulate both pathways concurrently may contribute to the relatively poor prognosis of leptomeningeal melanosis and the greater thickness and mitotic rate of melanomas with NRAS Q61 versus BRAF V600 mutations as well. An individual’s genome may also influence the occurrence and biological characteristics of CMNs. Kinsler et al., 2012Kinsler V.A. Abu-Amero S. Budd P. et al.Germline melanocortin-1-receptor genotype is associated with severity of cutaneous phenotype in congenital melanocytic nevi: a role for MC1R in human fetal development.J Invest Dermatol. 2012; 132: 2026-2032Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar have previously identified an increased frequency of CMNs, both small and large, in individuals with certain alleles of MC1R, encoding the melanocortin-1 receptor; these alleles are also associated with having red hair, fair skin, photosensitivity, and a propensity to develop acquired nevi and melanoma. Although mutations in NRAS, BRAF, and HRAS are known to activate the mitogen-activated protein kinase pathway and lead to melanocytic cell proliferation, these mutations also result in oncogene-induced senescence (OIS), which eventually ceases melanocytic proliferation unless overcome by other genetic aberrations. A number of mechanisms for OIS have been described, particularly (1) replicative senescence related to progressive shortening of telomeres; (2) oncogenic activation of P53 or P16 pathways; and (3) activation of DNA damage response pathways. The exclusive presence of NRAS mutations in giant and multiple CMNs, in contrast to the BRAF mutations seen in most small to medium-sized isolated CMNs or the HRAS mutations seen in ∼12% of Spitz nevi, suggest that activating mutations in NRAS induce a more prolonged phase than other Ras activating mutations of melanocytic proliferation before OIS, leading to more extensive skin involvement (Ichii-Nakato et al., 2006Ichii-Nakato N. Takata M. Takayanagi S. et al.High frequency of BRAFV600E mutation in acquired nevi and small congenital nevi, but low frequency of mutation in medium-sized congenital nevi.J Invest Dermatol. 2006; 126: 2111-2118Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). Elucidating the mechanism of OIS in large and multiple CMNs with NRAS mutations may provide insight into mechanisms of escape from senescence in all NRAS-mutated melanocytic neoplasms. In contrast to the relatively low risk of nevus transformation to melanoma with small CMNs, giant CMNs are recognized to have a lifetime risk of malignant transformation of ∼5%, with greater risk a function of nevus size and number of satellites (Alikhan et al., 2012Alikhan A. Ibrahimi O.A. Eisen D.B. Congenital melanocytic nevi: where are we now? Part I. Clinical presentation, epidemiology, pathogenesis, histology, malignant transformation, and neurocutaneous melanosis.J Am Acad Dermatol. 2012; 67: 495-517Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar. Most malignancies in giant CMNs occur during childhood. Indeed, of the patients described by Kinsler et al., 2013Kinsler V.A. Thomas A.C. Ishida M. et al.Multiple congenital melanocytic naevi and neurocutaneous melanosis are caused by post-zygotic mutations in codon 61 of NRAS.J Invest Dermatol. 2013; 132: 2229-2236Abstract Full Text Full Text PDF Scopus (211) Google Scholar transformation to melanoma occurred in a CMN in 1 of the 15 reported cases (6.7%) and in the leptomeningeal melanosis in 2 of 15. Presumably, increases in the number and duration of proliferative melanocytic cells result in a larger field of partially transformed cells that are primed for secondary events such as second gene mutations or chromosomal copy number changes needed for transformation. Giant CMNs also have a predilection toward the development of benign proliferative nodules. These expansile nodular proliferations of melanocytes often show worrisome histologic features, including cellular atypia and prominent mitotic activity. Histologic distinction from melanoma is often difficult. Studies with comparative genomic hybridization (CGH) have shown whole chromosomal changes, particularly loss of chromosomes 7, 9, or 10 (Bastian et al., 2002Bastian B.C. Xiong J. Frieden I.J. et al.Genetic changes in neoplasms arising in congenital melanocytic nevi: differences between nodular proliferations and melanomas.Am J Pathol. 2002; 161: 1163-1169Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar. These changes likely result in a temporary escape from OIS, but ultimately activate other mechanisms of cellular senescence and remain benign. In contrast, melanomas arising in CMNs typically harbor gains and losses of chromosomal fragments, in addition to whole chromosomal changes. A host of chromosomal copy number aberrations were seen by array CGH in both melanoma cases in the report of Kinsler et al., 2013Kinsler V.A. Thomas A.C. Ishida M. et al.Multiple congenital melanocytic naevi and neurocutaneous melanosis are caused by post-zygotic mutations in codon 61 of NRAS.J Invest Dermatol. 2013; 132: 2229-2236Abstract Full Text Full Text PDF Scopus (211) Google Scholar, including many gains and losses of chromosomal fragments, solidifying the diagnosis of melanoma. Interestingly, several recent studies have noted elevated expression of C-MYC, encoded on chromosome 8q24, as one key mechanism of overcoming RAS OIS (Hydbring et al., 2010Hydbring P. Bahram F. Su Y. et al.Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformation.Proc Natl Acad Sci USA. 2010; 107: 58-63Crossref PubMed Scopus (146) Google Scholar. This is supported by the gain in chromosome 8 in one of the NRAS-mutated melanomas described by Kinsler et al., 2013Kinsler V.A. Thomas A.C. Ishida M. et al.Multiple congenital melanocytic naevi and neurocutaneous melanosis are caused by post-zygotic mutations in codon 61 of NRAS.J Invest Dermatol. 2013; 132: 2229-2236Abstract Full Text Full Text PDF Scopus (211) Google Scholar and some of our own recent studies (Figure 2; P Gerami et al., unpublished data). Hence, cytogenetic analysis may help in more precisely identifying the development of melanoma and the precise extent of melanoma disease in patients with complex clinical phenotypes, including leptomeningeal melanocytosis. The case series by Kinsler et al., 2013Kinsler V.A. Thomas A.C. Ishida M. et al.Multiple congenital melanocytic naevi and neurocutaneous melanosis are caused by post-zygotic mutations in codon 61 of NRAS.J Invest Dermatol. 2013; 132: 2229-2236Abstract Full Text Full Text PDF Scopus (211) Google Scholar demonstrates that the combination of gene mutational analysis, cytogenetic analysis, and clinical phenotype may guide therapeutic strategies in the era of molecular diagnostics and targeted therapy. In contrast to the availability of vemurafenib for treating BRAF V600E+ metastatic melanoma, however, no currently available therapy specifically combats NRAS mutations. Nevertheless, targeting NRAS is a priority for melanoma research and for NCM, given the new recognition that virtually all harbor a Q61K or Q61R mutation. A systemically administered agent that traverses the blood–brain barrier would be required for management of neurologic involvement, but even a topically applied agent could be used for larger CMNs. Current strategies under consideration include: (1) inactivation of NRAS protein through pharmacological inhibition of membrane localization, which is required for RAS activity; (2) depletion of mutant NRAS protein specifically by small interfering RNA or antisense oligomers; and (3) targeting downstream signaling of the ERK and PI3K/AKT pathways (Kelleher and McArthur, 2012Kelleher F.C. McArthur G.A. Targeting NRAS in melanoma.Cancer J. 2012; 18: 132-136Crossref PubMed Scopus (61) Google Scholar. Elucidation of the mechanism by which OIS is overcome in melanomas arising in these neoplasms will also be an important step toward improved therapeutic targeting." @default.
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• W2033512653 title "Making a Mountain Out of a Molehill: NRAS, Mosaicism, and Large Congenital Nevi" @default.
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