Melanoma (MSK, NEJM 2014)

Overview

Whole-exome sequencing cohort of 64 patients with metastatic cutaneous melanoma (SKCM) treated with anti-CTLA-4 checkpoint blockade (ipilimumab or tremelimumab) at Memorial Sloan Kettering Cancer Center. Generated to investigate the genomic basis of response to CTLA-4 blockade, with a focus on tumor mutational load and neoantigen signatures as predictors of long-term clinical benefit. Sequencing was performed at MSKCC Genomics Core and the Broad Institute.

Composition

  • Cancer type: Cutaneous melanoma (SKCM), metastatic
  • Sample count: 64 patients; 128 exomes (tumor + matched blood/normal)
  • Cohort structure: Discovery set (25 patients: 11 long-term benefit, 14 minimal/no benefit); validation set (39 patients: 25 long-term benefit, 14 minimal/no benefit)
  • Treatment: 59 patients received ipilimumab; 5 received tremelimumab
  • Clinical outcome definition: Long-term benefit = radiographic freedom from disease or stable/decreased disease >6 months; minimal/no benefit = ≤6 months or progression on every CT
  • Reference genome: hg19

Assays / panels (linked)

  • whole-exome-seq: SureSelect Human All Exon 50-Mb capture (Agilent) → Illumina HiSeq 2000; mean tumor coverage 103×; >99% of target bases ≥10×

Papers using this cohort

  • PMID:25409260 — Snyder et al., New England Journal of Medicine 2014. “Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma.”

Notable findings derived from this cohort

  • High tumor mutational load (nonsynonymous exome mutations) was significantly associated with long-term clinical benefit from anti-CTLA-4 therapy in both discovery (P=0.01, Mann–Whitney) and validation (P=0.009, Mann–Whitney) cohorts; survival advantage for >100 nonsynonymous mutations was significant in the discovery set (P=0.04, log-rank) PMID:25409260.
  • A set of 101 shared tetrapeptide neoepitopes (identified by HLA-restricted MHC class I binding ≤500 nM using the NAseek algorithm) was exclusive to long-term benefiters in the discovery set and reproduced in the independent validation set; patients carrying the neoantigen signature had markedly longer overall survival (P<0.001 log-rank in both sets) PMID:25409260.
  • High mutation load alone did not guarantee response — several patients with >1,000 nonsynonymous mutations showed minimal/no benefit — indicating that neoantigen quality (pathogen-homologous tetrapeptides) provides additive predictive value beyond raw TMB PMID:25409260.
  • Two patient-specific neoantigens — TESPFEQHI (from FAM3C c.A577G, HLA-B4402 binder) and GLEREGFTF (from CSMD1 c.G10337A) — elicited polyfunctional IFN-γ+/TNF-α+ CD8+ T-cell responses ex vivo, providing experimental validation of the neoantigen-driven immune response model PMID:25409260.

Sources

  • cBioPortal study: skcm_mskcc_2014
  • EGA/dbGaP: available via cbioportal.org
  • Citation: Snyder et al. NEJM 2014 PMID:25409260

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