Ewing's sarcoma: diagnostic, prognostic, and therapeutic implications of molecular abnormalities

Abstract

The identification of the non-random chromosome rearrangements between the EWS gene on chromosome 22q12 and members of the ETS gene family in Ewing's sarcoma, peripheral primitive neuroectodermal tumour, Askin tumour, and neuroepithelioma has been a key advance in understanding their common histogenesis and defining the Ewing's sarcoma family of tumours (ESFT). In addition to improvements in diagnosis and potentially the stratification of patients for risk, biological investigations of these gene fusions may define targets for much needed therapeutic strategies to eliminate minimal residual disease or metastatic disease. Insight into their relation with other oncogenic events in ESFT will advance risk group analysis and ultimately may improve clinical management and survival for patients with this disease.

Figure 1

G banding of chromosomes from a Ewing’s sarcoma showing the t(11.22)(q12.24) translocation. This tumour is also characterised by trisomy of chromosome 8 and 12 and loss of chromosome 16, frequently described secondary aberrations in the Ewing’s sarcoma family of tumours. Reproduced with the permission of P Roberts, Department of Cytogenetics, St James’s University Hospital, Leeds, UK.

Figure 2

(A) Diagrammatical representation of the t(11;22) (q24;q12) translocation resulting in the generation of the EWS–FLI1 type 1 fusion transcript. (B) Cell cycle regulatory proteins implicated in regulation of the G1 checkpoint. 1. Despite the absence of cytogenetically detectable 9p21 chromosomal aberrations, p16 deletions are one of the most frequent secondary molecular aberrations identified to date in the Ewing’s sarcoma family of tumours (ESFT). 2. p53 is rarely mutated in primary ESFT, although mutation in this tumour suppressor gene has been described in up to 50% of ESFT cell lines. Mutation of p53 in ESFT is associated with a poor outcome for a small group of patients. 3. Mutation of the p21^WAF gene and/or downregulation of its nuclear expression is a common aberration in ESFT. For most tumours, loss of p21^WAF expression is independent of p53 status, suggesting gene silencing of WAF1 by mutation or hypermethylation. 4. Loss of pRb1 is rarely described in ESFT, but abrogation of the G1 checkpoint appears to be important in the progression and development of the ESFT clinical phenotype. Cdk, cyclin dependent kinase; Cyc, cyclin; pRb1, retinoblastoma protein 1; ppRb1, phosphorylated pRb1. (C) Potential strategies to exploit EWS–ETS gene rearrangements for therapeutic purposes.