Skin Cutaneous Melanoma (DFCI, Science 2015)

Overview

The skcm_dfci_2015 dataset is from Van Allen et al. (Science, 2015) and comprises pretreatment whole-exome sequencing of 110 metastatic melanoma patients treated with single-agent ipilimumab (anti-CTLA-4), with matched tumor RNA-seq for 42 (40 with matched WES). This is a landmark study establishing tumor mutational load and predicted neoantigen load as genomic correlates of clinical benefit from CTLA-4 blockade. Patients were stratified by RECIST response and overall survival. All sequencing data are deposited in dbGaP (phs000452.v2.p1).

Composition

  • 110 metastatic melanoma patients treated with ipilimumab monotherapy.
  • Histology: 92 cutaneous SKCM, 4 mucosal, 14 occult melanomas.
  • Clinical stratification: clinical benefit (CR/PR or SD with OS >1 yr, n=27); no clinical benefit (PD or SD with OS <1 yr, n=73); long-term-survival/early-progression (PFS <6 mo but OS >2 yr, n=10).
  • Average exome coverage: 183.7× (tumor), 157.2× (germline).
  • RNA-seq for 42 patients (40 with matched WES).
  • Reference genome: hg19.

Assays / panels (linked)

Papers using this cohort

  • PMID:26359337 — Van Allen et al. 2015, Science — “Genomic correlates of response to CTLA-4 blockade in metastatic melanoma.”
  • PMID:26997480 — Hugo et al. 2016, Cell: used as external reference cohort to validate that IPRES transcriptomic signature does NOT distinguish anti-CTLA-4 responders from non-responders (in contrast to its discrimination of anti-PD-1 response).

Notable findings derived from this cohort

  • Nonsynonymous mutational load (median 197 per sample) was significantly higher in clinical-benefit patients than non-benefit patients (P=0.0076, Mann-Whitney); association held in multivariate models controlling for prior RAF inhibitor and M class PMID:26359337.
  • Predicted neoantigen load (9–10 aa peptides, HLA class I binding ≤500 nM; median 369 per sample) was significantly associated with clinical benefit (P=0.027); highly correlated with mutational load (Spearman ρ=0.97) PMID:26359337.
  • Cytolytic activity signature (geometric mean of GZMA and PRF1 expression) was significantly elevated in clinical-benefit tumors (P=0.042); tumor CTLA4 expression (P=0.033) and PDCD1LG2 / PD-L2 expression (P=0.041) also higher in responders PMID:26359337.
  • Of 77,803 unique neoantigens, only 28 (~0.04%) were shared across benefit patients; no recurrent peptide sequence signature validated — response-associated neoantigens are overwhelmingly private events PMID:26359337.
  • No individual genes (including BRAF and NRAS) were enriched for nonsynonymous mutations in either response subgroup; clinical covariates (age, gender, histology, LDH) did not correlate with response PMID:26359337.
  • IPRES co-enrichment (26 transcriptomic signatures of mesenchymal transition/angiogenesis/wound-healing) was not differentially distributed between anti-CTLA-4 responders and non-responders in this cohort, arguing that innate resistance mechanisms differ between anti-PD-1 and anti-CTLA-4 checkpoint axes. PMID:26997480

Sources

  • Van Allen EM et al. “Genomic correlates of response to CTLA-4 blockade in metastatic melanoma.” Science. 2015;350(6257):207-211. PMID:26359337. DOI: 10.1126/science.aad0095.

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