Acral Melanoma (ACRM)

Overview

Acral melanoma (acral lentiginous melanoma, ALM) is a rare melanoma subtype arising on sun-shielded acral surfaces (palms, soles, nail beds). Unlike cutaneous melanoma (SKCM), it occurs predominantly in non-White populations and shows a worse prognosis. Genomically, it is dominated by structural variation (SVs) rather than UV-derived single-nucleotide variants, with a low UV mutational signature, low SNV burden (median 42 coding mutations per tumor), high SV burden (median 31 somatic breakpoints), and under-representation of canonical BRAF/NRAS/NF1 drivers. It occupies OncoTree position ACRM under MEL (Melanoma), skin tissue.

Cohorts in the corpus

  • mel_tsam_liang_2017 — 38 ALM tumors from 34 patients at Vanderbilt University and MSKCC; whole-exome sequencing (33 patients), long-insert whole-genome sequencing (31 patients), RNA-seq (33 patients), Sanger TERT promoter sequencing (28 patients); raw data deposited in dbGaP phs001036.v1.p1 PMID:28373299.

Recurrent alterations

  • TERT — aberrations in 41% (14/34) of patients, encompassing consensus CNV gains at the TERT-CLPTM1L locus (Chr 5p), promoter mutations in 4/28 (Chr5:1,295,113:G>A), one exonic missense (F919L), intronic SNV, and SV breakpoints in 4 patients; all patients with somatic TERT events expressed TERT; Telomerase Inhibitor IX produced ≥75% loss of viability in two primary ALM lines in vitro PMID:28373299.
  • PAK1 — focal copy gains in 5/34 (15%) patients, exclusively in BRAF/NRAS wild-type tumors (1 NF1-subtype, 4 triple-wild-type); validated by qPCR in 4/5; elevated PAK1 expression in 2/5; proposed as an alternative MAPK-pathway dysregulation route in triple-wild-type ALM PMID:28373299.
  • BRAF — mutated in 6/34 (18%) patients: V600E (4 patients, 12%), V600K+R462K (1), G466E (1); mutually exclusive of NRAS; UV signature present in 2 BRAF-mutant tumors PMID:28373299.
  • NRAS — 4 patients: Q61K (3, 9%), A59G (1); mutually exclusive of BRAF PMID:28373299.
  • NF1 — homozygous loss in 9% (3 patients); LOH plus E2578* nonsense in a fourth patient; combined prevalence 12% PMID:28373299.
  • CDKN2A — recurrent deletion (Chr 9), statistically significant in both primary and metastatic subsets PMID:28373299.
  • CDK4 — recurrent copy gain (Chr 12), significant in metastases PMID:28373299.
  • CLPTM1L — frequent SV breakpoints in 15% of patients and consensus copy gain on Chr 5p adjacent to TERT PMID:28373299.
  • ADCY2 — most-rearranged gene in the cohort: 32 breakpoints across 7 samples (21% of patients); partners include CLPTM1L, TERT, HECTD4, UBE2QL1 PMID:28373299.
  • MDM2 — copy gain in metastases only; MDM2:GNS and MDM2:CCT2 RNA fusions detected PMID:28373299.
  • KIT — single L576P mutation (1 patient) PMID:28373299.

Subtypes

  • BRAF/NRAS-mutant ALM (~29% combined): lower UV signature in most; 2 BRAF-mutant cases showed UV signature.
  • NF1-subtype ALM (~12%): homozygous NF1 loss or biallelic inactivation.
  • Triple-wild-type ALM (BRAF/NRAS/NF1-wild-type, ~59%): enriched for PAK1 copy gains (all 5 PAK1-gain patients were triple-wild-type or NF1-subtype) and structural variation PMID:28373299.

Therapeutic landscape

  • Telomerase Inhibitor IX — in vitro, 2.5 µM for 72 h reduced viability ≥75% in two primary ALM cell lines (TERT CNV gain and TERT promoter mutation) versus ~12% in normal melanocytes; authors propose TERT inhibition as a therapeutic strategy given limited targeted options in ALM PMID:28373299.
  • Ipilimumab / Pembrolizumab — immune checkpoint blockade administered to 22/34 patients; three complete responders had paradoxically low mutation (<75) and neo-antigen (<60) burdens, distinct from the pattern in cutaneous melanoma; response mechanism unclear PMID:28373299.
  • MAPK-directed therapy — BRAF/NRAS drivers actionable in ~29%; PAK1 copy gains (15%) nominated as an alternative MAPK target in triple-wild-type ALM PMID:28373299.

Sources

  • PMID:28373299 — Liang et al. 2017; integrated WES/LIWGS/RNA-seq of 38 ALM tumors; first comprehensive genomic landscape of ACRM.

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