Cutaneous Melanoma (SKCM)

Overview

SKCM is the OncoTree code for cutaneous (skin) melanoma. SKCM is a high-TMB malignancy driven primarily by UV-induced mutagenesis, with characteristic C>T transitions at dipyrimidines (SBS7 signature) and frequent activating mutations in BRAF, NRAS, and NF1.

Cohorts in the corpus

  • normal_skin_melanocytes_2024 — single-cell genotyping atlas of phenotypically normal skin melanocytes adjacent to a SKCM patient, profiling LowMut neural-crest-like vs HighMut UV-driven cell-of-origin programs. PMID:39975212

Recurrent alterations

  • BRAF, NRAS, NF1, TP53, PTEN, CDKN2A, TERT promoter mutations are canonical SKCM drivers.
  • The PMID:39975212 atlas characterizes precursor melanocyte transcriptomic states (MITF, MLANA, PMEL, TYRP1, AXL) that may seed SKCM cell-of-origin hypotheses.
  • WGS of 25 cutaneous melanoma tumors identified PREX2 as a recurrently mutated gene and confirmed KIT and BRAF alterations PMID:22622578
  • WES of 121 cutaneous melanomas (Broad) identified RAC1 P29S (3.9%), PPP6C (9%), and MAP2K1 as novel recurrently mutated genes; 83% of tumors harbored BRAF or NRAS hotspot mutations (mutually exclusive, p=3e-14) PMID:22817889
  • WES of 147 melanomas (Yale) found RAC1 P29S in 9.2% of sun-exposed cutaneous melanomas, PPP6C mutations in 12.4%, and NF1 inactivation in 30% of BRAF/NRAS-WT tumors; vemurafenib and dabrafenib cited as established BRAF-targeted therapies PMID:22842228
  • Whole-exome sequencing of 45 BRAF V600 metastatic cutaneous melanoma patients treated with vemurafenib or dabrafenib identified resistance alterations in 51% of cases; MAPK-pathway alterations (NRAS, BRAF amplification, MAP2K1, MAP2K2, MITF, NF1) accounted for 44% of patients. Novel resistance genes MAP2K2 (MEK2; 4 mutations) and MITF amplification were discovered and experimentally validated. Pre-treatment RAC1 P29S was enriched in early-resistance patients (3/14 vs 0 responders; P=0.026). PMID:24265153
  • Whole-exome sequencing of 64 metastatic SKCM patients treated with anti-CTLA-4 (ipilimumab/tremelimumab) showed high tumor mutational load was significantly associated with long-term clinical benefit (discovery P=0.01, validation P=0.009); a shared tetrapeptide neoepitope signature in responders predicted overall survival (P<0.001 log-rank in both cohorts) PMID:25409260.
  • TCGA integrative multi-platform profiling of 333 primary/metastatic SKCM (dataset: skcm_tcga_pub_2015) defined four genomic subtypes: BRAF-mutant (52%), RAS-mutant (28% NRAS), NF1-mutant (14%), and Triple-WT (14%); mean 16.8 mut/Mb — highest of any TCGA type; transcriptomic Immune subclass (51%) associated with significantly improved survival in regional metastases (log-rank P=0.003); bivariate LScore + LCK model proposed as a clinical-grade prognostic tool (HR=5.5, P=7.9e-5) PMID:26091043
  • Comprehensive genomic analysis of cutaneous melanoma revealed mutational landscape dominated by UV-signature mutations with recurrent alterations in BRAF, NRAS, and NF1 PMID:26359337
  • 38 pretreatment metastatic SKCM biopsies profiled by WES and RNA-seq to identify genomic and transcriptomic correlates of anti-PD-1 response; the IPRES mesenchymal/angiogenic transcriptional program defined innate resistance in 9/13 non-responders vs 1/15 responders, and BRCA2 LOF mutations were enriched in responders (28% vs 6%, Fisher P=0.002, OR=6.2) PMID:26997480
  • Cutaneous melanoma (SKCM) used as comparator to acral melanoma (ACRM): SKCM harbours canonical UV-signature BRAF/NRAS/NF1 drivers and higher mutation burden, contrasting with ACRM’s structural-variant dominance and UV-signature absence PMID:28373299
  • Riaz et al. profiled paired pre- and on-therapy biopsies from 68 advanced melanoma patients on anti-PD-1 (nivolumab, CA209-038 trial), demonstrating that pre-therapy TMB predicts OS in ipilimumab-naive but not ipilimumab-progressed patients, and that genomic contraction (selective depletion of neoantigenic clones on-therapy) in responders provides evidence of immunoediting under PD-1 blockade PMID:29033130
  • MC3 pan-cancer mutation-calling project (10,510 TCGA pairs) included SKCM; concordance with the legacy PanCan12 MAF exceeded 90%; SKCM had the largest median SNVs per sample along with LUSC and LUAD, consistent with UV-mutagen exposure PMID:29596782
  • Pan-cancer fusion study (9,624 TCGA samples) included SKCM; SKCM (melanoma) clustered in the neural-lineage arm-level group with GBM and LGG in the aneuploidy analysis; druggable fusions annotated across 29 cancer types including SKCM PMID:29617662

Subtypes

  • SKCM — cutaneous melanoma (this page).
  • See MEL for the umbrella melanoma OncoTree code spanning cutaneous, acral, mucosal, and uveal subtypes.

Therapeutic landscape

Sources

  • PMID:39975212 — normal skin melanocyte single-cell atlas (Tandukar et al.).

Page last touched by entity-page-writer on 2026-05-01.

This page was processed by crosslinker on 2026-05-14. - PMID:22622578

This page was processed by crosslinker on 2026-05-14. - PMID:22817889

This page was processed by crosslinker on 2026-05-14. - PMID:22842228

This page was processed by crosslinker on 2026-05-14. - PMID:24265153

This page was processed by crosslinker on 2026-05-14. - PMID:25409260

This page was processed by crosslinker on 2026-05-14. - PMID:26091043

This page was processed by crosslinker on 2026-05-14. - PMID:26359337

This page was processed by crosslinker on 2026-05-14. - PMID:26997480

  • PMID:28373299 — Liang et al. 2017; ACRM integrated genomics; SKCM used as comparator for UV-mutation-burden and BRAF/NRAS/NF1 driver landscape.

This page was processed by entity-page-writer on 2026-05-15. - PMID:29033130

This page was processed by wiki-cli on 2026-05-15. - PMID:29596782

This page was processed by wiki-cli on 2026-05-15. - PMID:29617662

This page was processed by wiki-cli on 2026-05-15.