Desmoplastic Melanoma (DESM)

Overview

Desmoplastic melanoma (DESM) is a rare, deeply invasive cutaneous melanoma variant characterized by prominent stromal desmoplasia and spindled neoplastic melanocytes. It sits at OncoTree level 3 under MEL (Melanoma), tissue: Skin. Desmoplastic melanoma is genetically distinct from common-type cutaneous melanoma: it carries an exceptionally high mutation burden (median 62 mutations/Mb) driven by a UV-radiation C>T mutational signature, yet is conspicuously devoid of canonical BRAF V600E and NRAS Q61K/R drivers. MAPK/PI3K pathway activation is instead achieved through a diverse, non-mutually-exclusive set of alterations in NF1, CBL, ERBB2, MAP2K1, MAP3K1, EGFR, and others, affecting 73% of tumors. The high TMB positions DESM as a strong candidate for immune checkpoint blockade.

Cohorts in the corpus

  • desm_broad_2015 — 62 desmoplastic melanomas: 20 fresh-frozen (discovery; 10 MSKCC, 10 Melanoma Institute Australia) with whole-genome + exome sequencing (13× and 89×), and 42 FFPE tumors (validation; UCSF) with targeted sequencing of 293 genes at 216× PMID:26343386.

Recurrent alterations

  • TERT — promoter mutations in 85% (17/20) of evaluable samples; overall TERT activation (promoter + amplification) in 90% of tumors PMID:26343386.
  • NFKBIE — novel recurrent promoter hotspot mutations in 14.5% of tumors (15/62); evidence for biallelic selection; not found in COSMIC or TCGA across any cancer type; proposed gain-of-function suppressing NFκB signaling PMID:26343386.
  • CDKN2A — focal deletions in 11/62 cases; LOF mutations; p16 loss confirmed by IHC PMID:26343386.
  • BRAF — V600E absent; kinase-impaired G466E/G469E/D594N substitutions in 3 tumors (paradoxically activate MAPK via CRAF) PMID:26343386.
  • NRAS — canonical Q61K/R absent; atypical Q61H in 1 tumor PMID:26343386.
  • NF1 — LOF mutations and focal deletions in 4 cases PMID:26343386.
  • CBL — frequent truncating/damaging missense mutations with no synonymous mutations; supports tumor-suppressor role PMID:26343386.
  • ERBB2 — recurrent S310F hotspot in 4/62 tumors PMID:26343386.
  • EGFR — focal amplifications in 3 tumors; IHC-confirmed overexpression PMID:26343386.
  • MAP2K1 — P124S/L hotspot in 2 tumors PMID:26343386.
  • MAP3K1 — focal amplifications in 3 tumors; novel finding in melanoma PMID:26343386.
  • PTPN11 — E76A/K hotspot in 2 tumors PMID:26343386.
  • MET — focal amplifications in 2 tumors; IHC-confirmed PMID:26343386.
  • RAC1 — P29S hotspot in 2 tumors PMID:26343386.
  • TP53 — top LOF-burden candidate; IHC-confirmed protein-level alteration PMID:26343386.
  • FBXW7 — truncating/WD-domain damaging mutations in 11% of tumors PMID:26343386.
  • ARID2, ARID1A — inactivating SWI/SNF mutations; ARID1A IHC-confirmed PMID:26343386.
  • RB1 — LOF mutations; IHC-confirmed protein loss PMID:26343386.
  • Extreme mutation burden (median 62 mutations/Mb) with dominant UV-radiation C>T signature (88% of mutations); older patients (>55 years) had significantly more mutations (p=2×10⁻³) PMID:26343386.

Subtypes

  • Pure and mixed desmoplastic subtypes are genetically similar based on the discovery/validation cohort analysis PMID:26343386.
  • Tumors from sun-shielded sites had the lowest mutation burdens; one such tumor carried a germline CDKN2A mutation PMID:26343386.

Therapeutic landscape

Sources

  • PMID:26343386 — Shain et al. (2015). Whole-genome, exome, and targeted sequencing of 62 desmoplastic melanomas; identified extreme mutation burden, UV signature, absence of BRAF V600E/NRAS canonical drivers, novel NFKBIE promoter hotspot, and diverse MAPK/PI3K activating alterations.

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