Acral Melanoma TSAM Cohort (Liang 2017)

Overview

Integrated whole-exome sequencing, long-insert whole-genome sequencing (LIWG), and RNA-seq analysis of 38 acral lentiginous melanoma (ALM) tumors from 34 patients enrolled at Vanderbilt University and Memorial Sloan-Kettering Cancer Center. This rare sun-shielded melanoma subtype was characterized by a low UV-signature SNV burden and high structural variant (SV) burden. Key findings include frequent TERT aberrations (41%) and PAK1 copy gains (15%) in BRAF/NRAS wild-type tumors. Raw sequencing deposited in dbGaP under accession phs001036.v1.p1.

Composition

• 38 ALM tumors from 34 patients — 3 patients contributed multiple tumors (patient 25: two metastases; patient 29: primary + two metastases; patient 34: primary + metastasis). Median tumor cellularity 50%.
• Tumor types: primary acral lentiginous melanomas and paired metastases; subsite includes plantar foot, fingers, palms.
• Comparator: TCGA cutaneous melanoma (SKCM) cohort used for landscape comparison.
• Cancer types: ACRM.

Assays / panels (linked)

• Whole-exome sequencing — 33 paired tumor/constitutional; 1 tumor-only. Somatic SNV calling required 2-of-3 callers (Seurat Q>30, MuTect, Strelka).
• Whole-genome sequencing — long-insert (~900 bp) LIWG for structural variant and CNV detection in 31 patients.
• RNA-seq — 33 patients; fusions detected with TopHat-Fusion; differential expression via Cufflinks/Cuffdiff and DESeq2.
• Sanger sequencing — TERT promoter interrogation in 28 patients (poorly covered by exome baits).
• Alignment: BWA (DNA), STAR (RNA).

Papers using this cohort

• PMID:28373299 — Liang et al. 2017, Nature Genetics: integrated multi-omic characterization of acral lentiginous melanoma; frequent TERT aberrations and PAK1 copy gains define this rare subtype.

Notable findings derived from this cohort

• Low SNV burden (median 42 somatic coding mutations per tumor) but high structural variant burden (median 31 somatic breakpoints per patient across 74% of patients); UV mutational signature largely absent (C>T at dipyrimidines only 39.4%) PMID:28373299.
• Only 29% of patients carried canonical BRAF/NRAS driver mutations, far below the rate in cutaneous melanoma; NF1 loss in 12% PMID:28373299.
• TERT aberrations (copy gains, promoter mutations, translocations, missense, or germline events) in 41% (14/34) of patients; Telomerase Inhibitor IX produced ≥75% loss of viability in two primary ALM cell lines carrying TERT alterations but not in normal melanocytes PMID:28373299.
• PAK1 focal copy gains in 15% (5/34) of patients, all BRAF/NRAS wild-type; validated by real-time PCR in 4/5, supporting PAK1 as an alternative MAPK-pathway dysregulation route in triple-wild-type ALM PMID:28373299.
• MAPK/PI3K pathway altered in 66% of patients; cell-cycle (CDK4/CDKN2A) in 51%; telomere maintenance (TERT) in 37%; apoptosis/senescence (MDM2/TP53) in 17% PMID:28373299.
• Among 22 patients receiving immune checkpoint blockade, three complete responders had low mutation (<75) and neo-antigen (<60) burdens — opposite of the cutaneous melanoma pattern PMID:28373299.
• Most-rearranged genes: ADCY2 (21% of patients) and CLPTM1L (15%); all ADCY2/CLPTM1L rearrangements occurred in BRAF wild-type tumors PMID:28373299.

Sources

• dbGaP accession: phs001036.v1.p1
• cBioPortal studyId: mel_tsam_liang_2017
• PMID:28373299

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