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Melanoma_in_Congenital_Melanocytic_Nevus

Disease Pathophysiology Research Report

2025-12-15
Falcon MONDO:0850110 Model: Edison Scientific Literature 21 citations

Disease Pathophysiology Research Report

Target Disease - Disease Name: Melanoma arising in Congenital Melanocytic Nevus (CMN), including CNS involvement (neurocutaneous melanocytosis, NCM) - MONDO ID: Not definitively assigned for the combined entity in retrieved sources (entity spans congenital melanocytic nevus and melanoma; leave blank pending curation) - Category: Skin Cancer

1) Core Pathophysiology: Current Understanding Melanoma arising within CMN is a developmental-oncologic process initiated by post-zygotic mosaic mutations in melanocytic lineage, most commonly NRAS codon 61 substitutions, with less frequent BRAF V600E and mosaic BRAF/RAF1 fusions. These events occur during embryogenesis in neural crest-derived melanocyte precursors or Schwann cell precursors, leading to clonal nevomelanocyte expansion in skin and, in some patients, parallel seeding of leptomeninges (NCM). Constitutive MAPK/ERK signaling is the central dysregulated pathway, with adaptive/compensatory activation of PI3K–AKT–mTOR contributing to survival and progression. Progression from nevus to melanoma typically requires additional alterations enabling telomere maintenance (TERT promoter activation), escape from oncogene-induced senescence (loss of CDKN2A/p16; TP53 pathway changes), and growth/invasion advantages (e.g., PTEN loss; copy-number gains such as NRAS amplification in select cases). Epigenomic reprogramming and distinct methylation profiles have been reported in pediatric malignant neurocutaneous melanocytic neoplasms, supporting a role for chromatin state in classification and possibly pathogenesis. Clinically, early CNS MRI abnormalities in infants with large/giant CMN correlate with higher risk of childhood melanoma and poor NCM outcomes. (Basu 2024, AntiCancer Research, Dec 2024, https://doi.org/10.21873/anticanres.17341; Salgado et al. 2025, Virchows Archiv, Jan 2025, https://doi.org/10.1007/s00428-024-04011-3; Kaminiow et al. 2025, Journal of Cancer Biology, Aug 2025, https://doi.org/10.46439/cancerbiology.6.075) (basu2024therapeuticstrategiesin pages 2-3, salgado2025congenitalmelanocyticneoplasms pages 3-4, salgado2025congenitalmelanocyticneoplasms pages 10-11, kaminiow2025oncogenicspecificityin pages 2-3, kaminiow2025oncogenicspecificityin pages 3-4)

Key dysregulated pathways and cellular processes include: - MAPK/ERK signaling: constitutive activation via NRAS Q61, BRAFV600E, and RAF fusions; downstream MEK/ERK drives proliferation and survival. (salgado2025congenitalmelanocyticneoplasms pages 3-4, basu2024therapeuticstrategiesin pages 2-3) - PI3K–AKT–mTOR signaling: cross-talk and compensatory activation, especially upon MEK inhibition; contributes to survival, invasion, and resistance. (salgado2025congenitalmelanocyticneoplasms pages 3-4, basu2024therapeuticstrategiesin pages 2-3) - Telomere maintenance: TERT promoter activation or amplification implicated in malignant transformation. (salgado2025congenitalmelanocyticneoplasms pages 3-4) - Senescence and cell cycle: nevi often undergo oncogene-induced senescence; progression entails CDKN2A/p16 loss and TP53 pathway disruption, enabling continued cycling. (basu2024therapeuticstrategiesin pages 2-3, kaminiow2025oncogenicspecificityin pages 2-3, hamed2025oncogenicdriversand pages 40-44) - Copy-number variation: includes NRAS amplification in some NCM-associated melanomas; broader CNA and LOH patterns associated with progression. (salgado2025congenitalmelanocyticneoplasms pages 10-11, kaminiow2025oncogenicspecificityin pages 2-3) - Epigenomic change: disease-specific methylation profiles reported in pediatric malignant neurocutaneous melanocytic neoplasms; supports diagnostic classification. (salgado2025congenitalmelanocyticneoplasms pages 10-11) - Microenvironment/growth factors: HGF/MET signaling enhances RAS→MAPK and PI3K–AKT pathways; increased mast cells reported in large/giant CMN. (basu2024therapeuticstrategiesin pages 2-3, salgado2025congenitalmelanocyticneoplasms pages 10-11) - Neurotropism/leptomeningeal spread: early mosaic mutation in neural crest/SCP lineages with seeding of leptomeninges explains NCM; diffuse meningeal melanomatosis often NRAS-driven, whereas circumscribed meningeal melanocytic tumors carry GNAQ/GNA11/SF3B1/EIF1AX/BAP1—useful for differential diagnosis. (Pellerino et al. 2024, Cancers, Jul 2024, https://doi.org/10.3390/cancers16142508) (basu2024therapeuticstrategiesin pages 2-3, salgado2025congenitalmelanocyticneoplasms pages 3-4, salgado2025congenitalmelanocyticneoplasms pages 10-11)

2) Key Molecular Players - Drivers and effectors (HGNC): NRAS (HGNC:7989), BRAF (HGNC:1097), RAF1 (HGNC:9829), MAP2K1/MEK1 (HGNC:6840), MAP2K2/MEK2 (HGNC:6842), TERT (HGNC:11730), CDKN2A/p16 (HGNC:1787), TP53 (HGNC:11998), PTEN (HGNC:9588), MET (HGNC:7029), HGF (HGNC:4886), MC1R (HGNC:6935), GNAQ (HGNC:4399), GNA11 (HGNC:4380), S1PR3 (HGNC:3169). (salgado2025congenitalmelanocyticneoplasms pages 3-4, basu2024therapeuticstrategiesin pages 2-3, salgado2025congenitalmelanocyticneoplasms pages 10-11) - Alterations: post-zygotic NRAS Q61K/R mosaic mutations (dominant in large/giant CMN/NCM), BRAFV600E in a subset, mosaic BRAF and RAF1 fusions (rare), MEK mutations in progressed disease, TERT promoter activation, CDKN2A loss, TP53 alterations, PTEN loss, occasional NRAS amplification in NCM-associated melanoma; rare S1PR3 variant in an NCM case. (salgado2025congenitalmelanocyticneoplasms pages 3-4, salgado2025congenitalmelanocyticneoplasms pages 10-11, basu2024therapeuticstrategiesin pages 2-3) - Cell types (CL): melanocytes (CL:0000148), neural crest cells (CL:0000133), Schwann cell precursors/Schwann cells (CL:0002573), mast cells (CL:0000097), tumor-associated macrophages (CL:0000235). (salgado2025congenitalmelanocyticneoplasms pages 10-11) - Anatomical locations (UBERON): skin (UBERON:0002097), epidermis (UBERON:0001003), dermis (UBERON:0002067), leptomeninx (UBERON:0002416), brain (UBERON:0000955). (basu2024therapeuticstrategiesin pages 2-3, salgado2025congenitalmelanocyticneoplasms pages 3-4) - Chemical entities (CHEBI) relevant to mechanism/therapy: trametinib (MEK inhibitor; CHEBI:75962), azacitidine (DNA methyltransferase inhibitor; CHEBI:47616), PI3K pathway inhibitors (e.g., alpelisib, CHEBI:90684; conceptually referenced as a class in reviews). Case reports and reviews describe MAPK inhibition benefit and emerging combined MAPK–PI3K strategies in NRAS-driven disease. (hamed2025oncogenicdriversand pages 40-44, salgado2025congenitalmelanocyticneoplasms pages 3-4)

Key molecular players artifact | Gene/Protein (HGNC) | Alteration / Mechanism | Pathway(s) | Role in CMN / Melanoma | Evidence (year, URL) | |---|---|---|---|---| | NRAS (NRAS) | Post‑zygotic activating codon‑61 mutations (Q61K/R) — mosaic in embryogenesis | MAPK/ERK; cross‑talk with PI3K‑AKT/mTOR | Dominant initiating driver in large/giant CMN and neurocutaneous melanocytosis (NCM); present in affected skin and CNS; predisposes to malignant progression when additional hits accumulate | 2025, https://doi.org/10.1007/s00428-024-04011-3 (salgado2025congenitalmelanocyticneoplasms pages 3-4), 2024, https://doi.org/10.21873/anticanres.17341 (basu2024therapeuticstrategiesin pages 2-3) | | BRAF (BRAF) | Somatic V600E in a subset of CMN; less commonly mosaic BRAF fusions | MAPK/ERK | Alternative initiator in some CMN with distinct histology and hyperproliferative phenotype; BRAF fusions act as mosaic drivers in select cases | 2025, https://doi.org/10.1007/s00428-024-04011-3 (salgado2025congenitalmelanocyticneoplasms pages 3-4), 2025 review (kaminiow2025oncogenicspecificityin pages 2-3) | | BRAF fusions (BRAF) | Mosaic gene fusions creating constitutively active BRAF fusion proteins | MAPK/ERK | Recurrent mosaic drivers in some CMN cases; potentially targetable by MAPK pathway inhibition | 2025, https://doi.org/10.1007/s00428-024-04011-3 (salgado2025congenitalmelanocyticneoplasms pages 3-4) | | RAF1 fusions (RAF1) | Oncogenic gene fusions activating RAF1 reported in rare CMN cases | MAPK/ERK | Rare alternative oncogenic event contributing to nevogenesis or atypical phenotypes | 2025, https://doi.org/10.1007/s00428-024-04011-3 (salgado2025congenitalmelanocyticneoplasms pages 3-4) | | MAP2K1 / MAP2K2 (MEK1/2) | Activating mutations or secondary pathway activation downstream of RAS/RAF | MAPK cascade (MEK→ERK) | Observed in progression/advanced lesions; contribute to constitutive MAPK signalling and are therapeutic targets (MEK inhibitors) | 2025 review (kaminiow2025oncogenicspecificityin pages 2-3) | | TERT promoter (TERT) | Promoter mutations or activation/amplification increasing telomerase expression | Telomere maintenance; replicative immortality | Associated with malignant transformation in melanocytic lesions, conferring proliferative advantage during progression from CMN to melanoma | 2025 review, https://doi.org/10.1007/s00428-024-04011-3 (salgado2025congenitalmelanocyticneoplasms pages 3-4) | | CDKN2A (CDKN2A / p16) | Deletion or loss of function leading to cell‑cycle checkpoint abrogation | Cell‑cycle regulation (G1/S) | Loss enables escape from oncogene‑induced senescence (OIS) and promotes malignant progression from CMN to invasive melanoma | 2025 review (kaminiow2025oncogenicspecificityin pages 2-3), clinical reports (hamed2025oncogenicdriversand pages 40-44) | | TP53 (TP53) | Somatic mutation/inactivation in progressed lesions | Cell cycle control, apoptosis, genome stability | Enriched in invasive/malignant CMN‑associated melanomas; contributes to genomic instability and progression | 2025 case/review (hamed2025oncogenicdriversand pages 40-44), 2025 review (salgado2025congenitalmelanocyticneoplasms pages 3-4) | | PTEN (PTEN) | Loss or inactivation leading to PI3K pathway activation | PI3K‑AKT‑mTOR | Cooperates with MAPK activation to promote survival, invasion, and therapy resistance in progressing CMN/melanoma | 2025, https://doi.org/10.1007/s00428-024-04011-3 (salgado2025congenitalmelanocyticneoplasms pages 3-4) | | MC1R (MC1R) | Germline variants acting as modifying risk alleles | Pigmentation and DNA‑damage response pathways | Germline modifier of melanoma susceptibility in patients with CMN; may influence phenotypic risk | 2025 clinical commentary (hamed2025oncogenicdriversand pages 40-44) | | HGF / MET (HGF, MET) | Paracrine/autocrine growth‑factor signalling amplifying RAS→MAPK and PI3K pathways | MAPK, PI3K‑AKT, PAK/STAT3 | Implicated experimentally in facilitating both skin and leptomeningeal melanocytic lesions and may enhance proliferation/motility (model of neurotropism) | 2024, https://doi.org/10.21873/anticanres.17341 (basu2024therapeuticstrategiesin pages 2-3) | | GNAQ / GNA11 (GNAQ, GNA11) | Activating Gq‑pathway mutations typical of uveal/meningeal melanocytic tumors | Gq → PKC / MAPK | Characteristic of circumscribed primary meningeal melanocytic tumors and distinct from NRAS‑driven diffuse NCM; useful for CNS differential diagnosis | 2025, https://doi.org/10.1007/s00428-024-04011-3 (salgado2025congenitalmelanocyticneoplasms pages 3-4) | | S1PR3 (S1PR3) | Rare somatic missense variant reported in an NCM case (candidate rare driver) | GPCR signalling with potential effects on migration/survival | Single‑case evidence implicates S1PR3 alteration in malignant progression within NCM; requires validation in larger series | 2024 case report (salgado2025congenitalmelanocyticneoplasms pages 10-11) |

Table: A compact, evidence‑linked markdown table listing major genes, mechanisms, pathways and their roles in CMN‑associated melanoma, with literature context IDs and URLs for source tracing.

3) Biological Processes (candidate GO terms) - MAPK cascade; positive regulation of ERK1/2 cascade; RAS protein signal transduction; regulation of cell cycle G1/S transition; negative regulation of cell cycle arrest; telomere maintenance via telomerase; cellular senescence; apoptotic process; melanocyte differentiation; neural crest cell migration; regulation of cell migration; response to UV; regulation of immune response. These processes map to the mechanistic axes described above (MAPK/PI3K, telomere/senescence, developmental migration, and immune context). (basu2024therapeuticstrategiesin pages 2-3, salgado2025congenitalmelanocyticneoplasms pages 3-4, salgado2025congenitalmelanocyticneoplasms pages 10-11)

4) Cellular Components (candidate GO terms) - Plasma membrane and lipid raft (RAS/RTK/GPCR initiation), cytosol (RAF–MEK–ERK), nucleus (ERK-regulated transcription, TP53, CDKN2A/p16), chromatin (epigenomic states), nucleoplasm/telomere (TERT-mediated maintenance), extracellular space (HGF, cytokines). (basu2024therapeuticstrategiesin pages 2-3, salgado2025congenitalmelanocyticneoplasms pages 3-4)

5) Disease Progression: Sequence of Events - Initiation (embryogenesis): post-zygotic mosaic mutation in NRAS Q61 (dominant) or less commonly BRAF V600 or BRAF/RAF1 fusion in neural crest–derived melanocytic lineage leading to clonal nevomelanocyte expansion in skin; parallel dissemination to leptomeninges yields asymptomatic melanocytosis in some infants. (salgado2025congenitalmelanocyticneoplasms pages 3-4, salgado2025congenitalmelanocyticneoplasms pages 10-11) - Nevus formation and growth arrest: constitutive MAPK signaling induces proliferation but often triggers oncogene-induced senescence (OIS), with p16 upregulation limiting growth. Lesion size/number reflect timing and cell-of-origin (earlier events → larger/multiple CMN and higher NCM risk). (basu2024therapeuticstrategiesin pages 2-3, kaminiow2025oncogenicspecificityin pages 3-4) - Progression to melanoma: acquisition of additional hits—TERT promoter activation, CDKN2A loss, TP53/PI3K–AKT–mTOR pathway changes (including PTEN loss), copy-number alterations (e.g., NRAS amplification)—enables senescence bypass, replicative immortality, invasion, and metastasis. Pediatric CNS-predominant disease (NCM) can progress to diffuse leptomeningeal melanomatosis with aggressive clinical behavior. (salgado2025congenitalmelanocyticneoplasms pages 10-11, kaminiow2025oncogenicspecificityin pages 2-3, basu2024therapeuticstrategiesin pages 2-3) - Clinical manifestations: rapid growth or new nodules within CMN, ulceration, and symptoms of CNS involvement (hydrocephalus, seizures) herald malignant transformation in a minority; early MRI abnormalities correlate with worse outcomes in NCM. (basu2024therapeuticstrategiesin pages 2-3, salgado2025congenitalmelanocyticneoplasms pages 3-4)

6) Phenotypic Manifestations (HP terms) - Multiple/large/giant congenital melanocytic nevi (HP:0001045, HP:0001050), hypertrichosis over nevi (HP:0002231), pigmentary mosaicism patterns (HP:0007518), neurocutaneous melanosis with leptomeningeal melanocytosis (HP:0006886), hydrocephalus (HP:0000238), seizures (HP:0001250), developmental delay (HP:0001263) in symptomatic NCM; malignant melanoma within CMN (HP:0009725). Clinical risk increases with giant lesions and early CNS abnormalities. (basu2024therapeuticstrategiesin pages 2-3, salgado2025congenitalmelanocyticneoplasms pages 3-4)

Recent Developments and Latest Research (2023–2024 priority) - Therapeutic insights in NCM: 2024 review synthesizes lack of standard therapies, highlights mosaic NRAS/BRAF biology, and preclinical rationale for targeting MAPK and PI3K–AKT–mTOR; documents poor outcomes in symptomatic NCM and risks associated with CSF shunting (including peritoneal seeding). (Basu 2024, AntiCancer Research, Dec 2024, https://doi.org/10.21873/anticanres.17341) (basu2024therapeuticstrategiesin pages 2-3) - Differential CNS melanocytic tumor genetics: 2024 EURACAN review delineates NRAS/BRAF in diffuse leptomeningeal disease versus GNAQ/GNA11/SF3B1/EIF1AX/BAP1 in circumscribed primary meningeal melanocytic tumors—important for diagnosis and management. (Pellerino et al. 2024, Cancers, Jul 2024, https://doi.org/10.3390/cancers16142508) (basu2024therapeuticstrategiesin pages 2-3) - 2025 updates (relevant to 2023–2024 themes): comprehensive review of congenital melanocytic neoplasms consolidates evidence for NRAS Q61 mosaicism, the emergence of mosaic BRAF fusions as recurrent drivers, MAPK/PI3K pathway crosstalk, epigenomic classification, and reports of NRAS amplification in NCM-associated melanoma. Though 2025, it aggregates 2023–2024 literature. (Salgado et al. 2025, Virchows Archiv, Jan 2025, https://doi.org/10.1007/s00428-024-04011-3) (salgado2025congenitalmelanocyticneoplasms pages 3-4, salgado2025congenitalmelanocyticneoplasms pages 10-11)

Current Applications and Real-World Implementations - Molecular diagnostics: hotspot testing for NRAS Q61 and BRAF V600 in CMN and associated tumors; fusion testing (BRAF, RAF1) in atypical cases; use of methylation profiling in challenging pediatric melanocytic neoplasms for classification. (salgado2025congenitalmelanocyticneoplasms pages 3-4, salgado2025congenitalmelanocyticneoplasms pages 10-11) - Imaging risk stratification: early-life brain/spine MRI in infants with large/giant CMN and multiple satellites to identify CNS melanocytosis and stratify risk. (basu2024therapeuticstrategiesin pages 2-3, salgado2025congenitalmelanocyticneoplasms pages 3-4) - Targeted therapy experience: case-level and small-series experience with MEK inhibition (e.g., trametinib) in NRAS-mutant CMN/NCM; combination strategies exploring MAPK plus epigenetic therapy (e.g., azacitidine) have shown transient responses with resistance. These approaches derive from the centrality of MAPK signaling and adaptive PI3K activation. (hamed2025oncogenicdriversand pages 40-44, basu2024therapeuticstrategiesin pages 2-3, salgado2025congenitalmelanocyticneoplasms pages 3-4)

Expert Opinions and Authoritative Analyses - Reviews emphasize that CMN-associated melanoma is mechanistically distinct from conventional UV-driven adult cutaneous melanoma, with early embryonic mosaic drivers (NRAS/BRAF) and lower UV-signature mutational contexts; progression relies on telomere, cell-cycle, and PI3K alterations, and epigenomic state. Interdisciplinary management, molecular testing, and surveillance are recommended, with research priorities in faithful modeling and rational combination therapy. (basu2024therapeuticstrategiesin pages 2-3, salgado2025congenitalmelanocyticneoplasms pages 3-4, kaminiow2025oncogenicspecificityin pages 2-3)

Relevant Statistics and Data - Driver prevalence: NRAS Q61 is dominant in large/giant CMN (≈68–77% in aggregated series; up to ~90% in the very largest lesions), while BRAF V600 is a minority driver; mosaic BRAF fusions/RAF1 fusions are rare but recurrent. (Salgado 2025; Kaminiow 2025) (salgado2025congenitalmelanocyticneoplasms pages 3-4, kaminiow2025oncogenicspecificityin pages 3-4) - NCM burden and outcomes: a meta-analysis summarized in a 2024 review reports leptomeningeal melanoma in a minority of NCM (≈9% of NCM overall), with most symptomatic NCM patients requiring shunting and experiencing poor survival; peritoneal seeding via VP shunt is a recognized complication. (Basu 2024) (basu2024therapeuticstrategiesin pages 2-3) - Risk stratification: early MRI abnormalities within the first months of life predict worse outcomes and higher childhood melanoma risk in giant CMN/NCM. (Salgado 2025; Basu 2024) (basu2024therapeuticstrategiesin pages 2-3, salgado2025congenitalmelanocyticneoplasms pages 1-3, salgado2025congenitalmelanocyticneoplasms pages 3-4)

Structured Knowledge Base Annotations - Genes/Proteins (HGNC): NRAS (HGNC:7989); BRAF (HGNC:1097); RAF1 (HGNC:9829); MAP2K1 (HGNC:6840); MAP2K2 (HGNC:6842); TERT (HGNC:11730); CDKN2A (HGNC:1787); TP53 (HGNC:11998); PTEN (HGNC:9588); MC1R (HGNC:6935); MET (HGNC:7029); HGF (HGNC:4886); GNAQ (HGNC:4399); GNA11 (HGNC:4380); S1PR3 (HGNC:3169). (salgado2025congenitalmelanocyticneoplasms pages 3-4, basu2024therapeuticstrategiesin pages 2-3, salgado2025congenitalmelanocyticneoplasms pages 10-11) - Biological Processes (GO): MAPK cascade (GO:0000165); positive regulation of ERK1/ERK2 cascade (GO:0070374); PI3K signaling (GO:0014065); G1/S transition of mitotic cell cycle (GO:0044843); regulation of telomere maintenance via telomerase (GO:1904356); cellular senescence (GO:0090398); melanocyte differentiation (GO:0030318); neural crest cell migration (GO:0014037); response to UV (GO:0009411); regulation of immune response (GO:0050776). (basu2024therapeuticstrategiesin pages 2-3, salgado2025congenitalmelanocyticneoplasms pages 3-4, salgado2025congenitalmelanocyticneoplasms pages 10-11) - Cellular Components (GO): plasma membrane (GO:0005886); cytosol (GO:0005829); nucleus (GO:0005634); chromatin (GO:0000785); telomere (GO:0000781); extracellular space (GO:0005615). (basu2024therapeuticstrategiesin pages 2-3, salgado2025congenitalmelanocyticneoplasms pages 3-4) - Cell Types (CL): melanocyte (CL:0000148); neural crest cell (CL:0000133); Schwann cell (CL:0002573); mast cell (CL:0000097); macrophage (CL:0000235). (salgado2025congenitalmelanocyticneoplasms pages 10-11) - Anatomical Locations (UBERON): skin (UBERON:0002097); epidermis (UBERON:0001003); dermis (UBERON:0002067); leptomeninx (UBERON:0002416); brain (UBERON:0000955). (basu2024therapeuticstrategiesin pages 2-3, salgado2025congenitalmelanocyticneoplasms pages 3-4) - Chemical Entities (CHEBI): trametinib (CHEBI:75962); azacitidine (CHEBI:47616); alpelisib (CHEBI:90684) [class exemplar for PI3K inhibition discussed]. (hamed2025oncogenicdriversand pages 40-44, salgado2025congenitalmelanocyticneoplasms pages 3-4) - Evidence items (selected, with URLs and publication dates): • Basu D. Therapeutic Strategies in Neurocutaneous Melanocytosis. AntiCancer Research. Dec 2024. https://doi.org/10.21873/anticanres.17341. (basu2024therapeuticstrategiesin pages 2-3) • Salgado CM, Tomás-Velázquez A, Reyes-Múgica M. Congenital melanocytic neoplasms: clinical, histopathological and recent molecular developments. Virchows Archiv. Jan 2025. https://doi.org/10.1007/s00428-024-04011-3. (salgado2025congenitalmelanocyticneoplasms pages 3-4, salgado2025congenitalmelanocyticneoplasms pages 10-11) • Kaminiow K, Ostrowski SM, Fisher DE. Oncogenic specificity in nevus and melanoma formation. Journal of Cancer Biology. Aug 2025. https://doi.org/10.46439/cancerbiology.6.075. (kaminiow2025oncogenicspecificityin pages 2-3, kaminiow2025oncogenicspecificityin pages 3-4) • Pellerino A, et al. Primary Meningeal Melanocytic Tumors… EURACAN. Cancers. Jul 2024. https://doi.org/10.3390/cancers16142508. (basu2024therapeuticstrategiesin pages 2-3) • Hamed E. Oncogenic drivers and therapeutic vulnerabilities in pediatric rhabdomyosarcoma and melanoma. 2025. (hamed2025oncogenicdriversand pages 40-44)

Notes on direct quotes - Wherever possible, claims are directly tied to peer-reviewed 2023–2024 reviews and primary reports. Direct quotations were limited by the retrieved excerpt format; verbatim diagnostic criteria and prevalence ranges are paraphrased with precise citations and URLs.

Conclusions Melanoma arising in CMN is a mosaic, developmentally rooted malignancy classically driven by NRAS Q61 (and less commonly BRAF V600 or BRAF/RAF1 fusions), converging on MAPK signaling with PI3K–AKT/mTOR cooperation. Progression requires senescence bypass (CDKN2A/TP53), telomere activation (TERT), and additional genomic/epigenomic changes, with neurotropic dissemination reflecting early neural crest lineage involvement. These mechanistic insights support risk stratification (early MRI), molecular diagnostics (NRAS/BRAF hotspots, fusions, methylation profiling), and rational targeted approaches (MEK ± PI3K/epigenetic combinations), though robust clinical evidence in NCM remains limited and outcomes poor, underscoring the need for prospective registries and trials. (basu2024therapeuticstrategiesin pages 2-3, salgado2025congenitalmelanocyticneoplasms pages 3-4, salgado2025congenitalmelanocyticneoplasms pages 10-11)

References

  1. (basu2024therapeuticstrategiesin pages 2-3): DIPANJAN BASU. Therapeutic strategies in neurocutaneous melanocytosis. AntiCancer Research, 44:5157-5167, Dec 2024. URL: https://doi.org/10.21873/anticanres.17341, doi:10.21873/anticanres.17341. This article has 1 citations and is from a peer-reviewed journal.

  2. (salgado2025congenitalmelanocyticneoplasms pages 3-4): Claudia Maria Salgado, Alejandra Tomás-Velázquez, and Miguel Reyes-Múgica. Congenital melanocytic neoplasms: clinical, histopathological and recent molecular developments. Virchows Archiv, 486:165-176, Jan 2025. URL: https://doi.org/10.1007/s00428-024-04011-3, doi:10.1007/s00428-024-04011-3. This article has 5 citations and is from a peer-reviewed journal.

  3. (salgado2025congenitalmelanocyticneoplasms pages 1-3): Claudia Maria Salgado, Alejandra Tomás-Velázquez, and Miguel Reyes-Múgica. Congenital melanocytic neoplasms: clinical, histopathological and recent molecular developments. Virchows Archiv, 486:165-176, Jan 2025. URL: https://doi.org/10.1007/s00428-024-04011-3, doi:10.1007/s00428-024-04011-3. This article has 5 citations and is from a peer-reviewed journal.

  4. (salgado2025congenitalmelanocyticneoplasms pages 10-11): Claudia Maria Salgado, Alejandra Tomás-Velázquez, and Miguel Reyes-Múgica. Congenital melanocytic neoplasms: clinical, histopathological and recent molecular developments. Virchows Archiv, 486:165-176, Jan 2025. URL: https://doi.org/10.1007/s00428-024-04011-3, doi:10.1007/s00428-024-04011-3. This article has 5 citations and is from a peer-reviewed journal.

  5. (kaminiow2025oncogenicspecificityin pages 2-3): Konrad Kaminiow, Stephen M Ostrowski, and David E. Fisher. Oncogenic specificity in nevus and melanoma formation. Journal of Cancer Biology, 6:64-70, Aug 2025. URL: https://doi.org/10.46439/cancerbiology.6.075, doi:10.46439/cancerbiology.6.075. This article has 0 citations.

  6. (kaminiow2025oncogenicspecificityin pages 3-4): Konrad Kaminiow, Stephen M Ostrowski, and David E. Fisher. Oncogenic specificity in nevus and melanoma formation. Journal of Cancer Biology, 6:64-70, Aug 2025. URL: https://doi.org/10.46439/cancerbiology.6.075, doi:10.46439/cancerbiology.6.075. This article has 0 citations.

  7. (hamed2025oncogenicdriversand pages 40-44): E Hamed. Oncogenic drivers and therapeutic vulnerabilities in pediatric rhabdomyosarcoma and melanoma. Unknown journal, 2025.