Gene expression profiling of Ewing sarcoma tumours reveals the prognostic importance of tumour-stromal interactions: A report from the Children's Oncology Group

Abstract

Relapse of Ewing sarcoma (ES) can occur months or years after initial remission, and salvage therapy for relapsed disease is usually ineffective. Thus, there is great need to develop biomarkers that can predict which patients are at risk for relapse so that therapy and post-therapy evaluation can be adjusted accordingly. For this study, we performed whole genome expression profiling on two independent cohorts of clinically annotated ES tumours in an effort to identify and validate prognostic gene signatures. ES specimens were obtained from the Children's Oncology Group and whole genome expression profiling performed using Affymetrix Human Exon 1.0 ST arrays. Lists of differentially expressed genes between survivors and non-survivors were used to identify prognostic gene signatures. An independent cohort of tumours from the Euro-Ewing cooperative group was similarly analysed as a validation cohort. Unsupervised clustering of gene expression data failed to segregate tumours based on outcome. Supervised analysis of survivors versus non-survivors revealed a small number of differentially expressed genes and several statistically significant gene signatures. Gene-specific enrichment analysis demonstrated that integrin and chemokine genes were associated with survival in tumours where stromal contamination was present. Tumours that did not harbour stromal contamination showed no association of any genes or pathways with clinical outcome. Our results reflect the challenges of performing RNA-based assays on archived bone tumour specimens. In addition, they reveal a key role for tumour stroma in determining ES prognosis. Future biological and clinical investigations should focus on elucidating the contribution of tumour:micro-environment interactions on ES progression and response to therapy.