Melanoma (MEL)

Overview

Melanoma (OncoTree code MEL, parent SKIN) is a malignant neoplasm of melanocytes. In the corpus, melanoma appears primarily in the context of CNS metastases and CSF circulating tumor DNA profiling.

Cohorts in the corpus

  • csf_msk_2024: Melanoma patients with CNS involvement were included in the MSK CSF ctDNA cohort (1,007 CSF samples from 711 patients across >90 tumor types) PMID:39289779.
  • Epidemiologic cohort (Northwestern University): 2,934 tanning bed users vs. 2,929 controls; exome sequencing of 182 single melanocytes from 26 donors. Dataset: normal_skin_melanocytes_2024. PMID:38895302
  • Pan-cancer liquid biopsy VTE cohort (MSK): melanoma comprised 7% of the 4,141-patient discovery cohort profiled by MSK-ACCESS. Dataset: msk_ctdna_vte_2024. PMID:39147831
  • ATLAS classifier validation set: melanoma included in 22-class cancer site-of-origin and 8-class lineage models. PMID:27634761
  • MSK pan-cancer BRAF fusion study: MEL represented as a histology within the 97,024-sample cohort; TERT mutations co-occurred with BRAF fusions in 64% of melanomas. PMID:38922339

Recurrent alterations

  • BRAF p.V600E detected in CSF ctDNA from melanoma patients with leptomeningeal disease PMID:39289779.
  • BRAF fusions (non-V600E): TERT mutations co-occur with BRAF fusions in 64% of melanoma BRAF fusion cases; melanoma is among the histologies in which BRAF fusions occur at low frequency as de novo or acquired events. PMID:38922339
  • TP53 was the most frequently altered gene across all tumor types in the CSF ctDNA cohort (49% of ctDNA-positive samples), including melanoma PMID:39289779.
  • NF1 — most frequently pathogenically mutated gene in normal melanocytes from tanning bed users; multiple loss-of-function mutations observed. PMID:38895302
  • BRAF L597R and G466R pathogenic mutations identified in melanocytes from tanning cohort donors. PMID:38895302
  • COSMIC mutational signature 11 significantly enriched in tanning bed users’ melanocytes (P=0.0405), distinct from standard UV SBS7a signature. PMID:38895302
  • CCLE pharmacogenomic profiling included melanoma cell lines among 947 lines tested across 24 drugs; elastic-net models predicted drug sensitivity from genomic features PMID:22460905
  • WGS of 25 melanoma tumors identified PREX2 as a recurrently mutated driver and characterized KIT and BRAF alteration patterns PMID:22622578
  • WES of 121 melanomas (Broad) identified MAP2K1, PPP6C, and RAC1 P29S as novel significantly mutated genes; median somatic mutation rate of 14.4/Mb with 82% UV-signature C>T transitions PMID:22817889
  • WES of 147 melanomas (Yale) confirmed RAC1 P29S in 9.2% of sun-exposed tumors (third most common driver after BRAF/NRAS) and PPP6C mutations in 12.4% of sun-exposed tumors; three molecular melanoma classes defined by mutation burden and copy-number profile PMID:22842228
  • Anti-PD-1 response genomics in 38 metastatic melanoma cases: IPRES transcriptional co-enrichment (mesenchymal transition, angiogenesis, hypoxia) marked innate resistance independently of mutational load; BRCA2 LOF mutations enriched in responders (OR=6.2) PMID:26997480
  • In the MSK-IMPACT pan-cancer cohort, TERT promoter mutations were present in 49% of melanoma (predominantly cutaneous); UV mutation signatures predominated in melanoma; 56% of MEL patients harbored an OncoKB-actionable alteration (4th highest); a novel recurrent CDK5RAP2-BRAF fusion was identified in two melanomas; 75 non-melanoma BRAF V600 patients showed identical 71% clinical-benefit rate to melanoma BRAF V600 patients on BRAF-targeted therapy. PMID:28481359

Subtypes

  • Metastatic melanoma with CNS involvement (brain metastases and leptomeningeal disease) represented in the CSF ctDNA cohort PMID:39289779.
  • Indoor tanning creates melanoma risk profile resembling familial melanoma: early onset, multiple primaries, and broad field of at-risk melanocytes. Tanning bed users had elevated melanoma risk (OR 2.0, 95% CI 1.38–2.98) after adjusting for age, family history, and sunburn history, with dose-dependent relationship (P<0.0001). PMID:38895302
  • Lineage de-differentiation score was prognostic for survival in primary melanoma (HR 0.0001, P=0.001) and metastatic melanoma (HR 0.31, P=0.033) in the ATLAS classifier study. PMID:27634761

Therapeutic landscape

  • 50.7% of ctDNA-positive CSF samples across all tumor types carried a level 1 OncoKB actionable alteration; BRAF V600E in melanoma is a level 1 actionable target PMID:39289779.
  • UV mutational signatures identified in CSF ctDNA from melanoma samples (n=3 among 35 high-TMB samples), aiding confirmation of melanoma as the primary tumor site PMID:39289779.
  • ctDNA detection associated with higher VTE risk (HR=2.49) in pan-cancer cohort including melanoma (7% of discovery cohort); anticoagulation associated with lower VTE in ctDNA-positive patients (adjusted HR=0.50). PMID:39147831
  • Marketing claims that tanning beds are safer than sunlight are contradicted by elevated mutation burden specifically in low-CSD body sites; distinct signature 11 may serve as molecular marker to distinguish tanning-bed-induced melanomas. PMID:38895302

Sources

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