SKCM TCGA 2015 (TCGA Melanoma Working Group)

Overview

Comprehensive multi-platform genomic characterization of 333 cutaneous melanomas (67 primary, 266 metastatic) from 331 adult patients across 14 tissue source sites, published by the TCGA Network in Cell 2015 (PMID:26091043). The study applied six molecular platforms to a core set of 199 samples and whole-exome sequencing to 320 samples. Cutaneous melanoma carries the highest mutation burden of any TCGA tumor type (mean 16.8 mutations/Mb), driven primarily by UV-signature C>T substitutions. Raw data available at GDAC Firehose stddata__2013_11_14 and the TCGA SKCM Data Portal.

Composition

  • N = 333 cutaneous melanoma samples from 331 adult patients; 67 (20%) primary, 266 (80%) metastatic.
  • Metastasis sites: 160 regional lymph nodes, 52 regional skin/soft tissue, 35 distant.
  • Cancer type: SKCM.
  • Median primary thickness: 2.7 mm (mean 4.9 mm).
  • Complete six-platform data available for 199 samples; WES for 320 samples (318 with paired germline).

Assays / panels (linked)

  • whole-exome-seq — 320 samples; Agilent SureSelect Human All Exon v2.0 44 Mb; Illumina HiSeq 2×76 bp paired-end; ~87× mean exon coverage. Reads aligned with bwa/Picard/Firehose.
  • whole-genome-sequencing — deep WGS on 38 samples; low-pass WGS on 119 samples.
  • affymetrix-snp6 — DNA copy-number profiling on 333 samples; purity/ploidy via absolute.
  • rna-seq — mRNA sequencing on 331 samples (Illumina mRNA TruSeq, HiSeq 2000).
  • mirna-seq — microRNA sequencing on 323 samples.
  • 450k-methylation-array — DNA methylation profiling on 333 samples (Illumina 450K).
  • rppa — reverse-phase protein array (181 cancer-related proteins/phosphoproteins) on 202 samples.
  • sanger-sequencing — TERT promoter C228T/C250T PCR-Sanger sequencing in 115 samples.
  • mutsig — significantly mutated gene discovery (Q < 0.1).
  • icluster — multi-platform integrative subtype discovery.
  • shatterseek — complex structural rearrangement detection.

Papers using this cohort

  • PMID:26091043 — TCGA Network, Cell 2015: genomic classification of cutaneous melanoma; primary discovery study for this cohort.
  • PMID:26997480 — Hugo et al. 2016, Cell: used as external reference to show IPRES co-enrichment is more prevalent in metastatic SKCM (90/282 metastatic) vs primary cutaneous tumors (6/69).

Notable findings derived from this cohort

  • Four genomic subtypes defined by dominant driver: BRAF (52%), RAS (28%, predominantly NRAS), NF1 (14%), and Triple-WT (no hot-spot BRAF/RAS/NF1); all three named subtypes show UV-signature prevalence >90% while Triple-WT is only 30% UV-signature. PMID:26091043
  • Mean mutation burden 16.8 mut/Mb — highest of any TCGA tumor type at the time; 76–84% of samples carry a UV mutational signature. PMID:26091043
  • Three transcriptomic subclasses with prognostic significance: Immune (51%, favorable outcome), Keratin (31%, worst outcome), MITF-low (18%); high lymphocyte score + Immune subclass + high LCK expression form a tri-feature prognostic model (log-rank P=8.0e–6) in regional metastases. PMID:26091043
  • TERT promoter C228T enriched in BRAF (75%), RAS (72%), NF1 (83%) subtypes but depleted in Triple-WT (6.7%), which activates TERT via amplification or structural rearrangement instead. PMID:26091043
  • KIT mutations and 4q12 focal amplifications (KIT/PDGFRA/KDR) enriched in Triple-WT subtype; CD274 (PD-L1) focal amplifications in BRAF subtype — each subtype presents distinct therapeutic opportunities. PMID:26091043
  • 224 candidate fusion drivers identified; Triple-WT enriched for complex structural rearrangements (ShatterSeek p=0.00098) and driver fusions involving AKT3, RAF1, MITF, and HMGA2. PMID:26091043
  • IPRES (Innate anti-PD-1 Resistance) co-enrichment significantly over-represented in metastatic vs primary cutaneous tumors: 90/282 metastatic vs 6/69 primary (P=3.9e-5, OR=0.2 for primary vs metastatic), consistent with IPRES marking metastasis-associated mesenchymal programs. PMID:26997480

Sources

  • cBioPortal study: skcm_tcga_pub_2015
  • GDAC Firehose: stddata__2013_11_14
  • TCGA SKCM Data Portal

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