Ewing Sarcoma — Institut Curie / St. Jude 2014

Overview

Whole-genome sequencing study of Ewing sarcoma tumors generated by a joint Institut Curie / St. Jude collaboration (Tirode et al., 2014). The discovery arm profiled 112 tumor/normal pairs by Illumina HiSeq2000 WGS (median 35× tumor, 25× germline); a follow-up targeted arm profiled 199 additional French Ewing sarcoma patients treated under the EuroEwing99 protocol for STAG2 and TP53 status. Combined clinical cohort: 299 patients with overall-survival data. Raw data deposited in EGA under accessions EGAS00001000855 (Institut Curie) and EGAS00001000839 (St. Jude).

Composition

  • Cancer type: ES (Ewing sarcoma).
  • Discovery cohort: 112 fresh-frozen tumor/matched germline pairs; 80% tumor purity >70%.
  • Follow-up cohort: 199 FFPE/fresh samples, targeted capture of STAG2 and TP53.
  • Combined clinical cohort: 299 patients with overall-survival data.
  • Cell line panel: 19 Ewing sarcoma cell lines (A673, RD-ES, SK-ES-1, SK-N-MC, MHH-ES1, TC-71, EW-1/3/7/16/18/22/23, STA-ET-1/3/8, MIC, ORS, POE).

Assays / panels (linked)

  • whole-genome-seq — paired-end, Illumina HiSeq2000; GRCh37-lite; BWA alignment.
  • targeted-dna-seq — targeted capture of STAG2 and TP53 on the follow-up cohort.
  • CREST for structural-variant calling; CONSERTING for copy-number analysis.
  • genome-MuSiC for significantly mutated gene testing.

Papers using this cohort

  • PMID:25223734 — Tirode et al. (2014), Cancer Discovery. Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations.

Notable findings derived from this cohort

  • Ewing sarcoma has a low background mutation rate (median 10 coding mutations/tumor); STAG2 (17%), CDKN2A (12%), TP53 (7%), EZH2/BCOR/ZMYM3 (~2.7% each) are the most frequently mutated genes beyond the obligate EWSR1-ETS fusion PMID:25223734.
  • STAG2 and CDKN2A alterations are mutually exclusive; STAG2 and TP53 mutations co-associate significantly (P = 2.4×10⁻⁴) and together define a high-risk subtype with markedly inferior overall survival in 299 patients PMID:25223734.
  • Chr 1q gain and chr 16q loss (co-associated via unbalanced t(1;16)) each independently confer shorter overall survival (P = 2×10⁻⁵ and P = 0.0037, log-rank) PMID:25223734.
  • Subclonal STAG2 mutations at diagnosis can expand to dominate the clonal architecture at relapse, implicating STAG2 as a clonal-evolution biomarker PMID:25223734.
  • Chromothripsis observed in 5/112 cases, enriched in EWSR1-ERG–fused tumors PMID:25223734.

Sources

  • EGA: EGAS00001000855 (Institut Curie), EGAS00001000839 (St. Jude).
  • cBioPortal study: es_iocurie_2014.

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