Background: Ewing sarcoma family tumors (EFT) express EWS-FLI1 or a related chimeric oncogene. Although additional cooperative molecular events are necessary for transformation the identity of these hits and the precise cellular origins of EFT remain uncertain. Patients who present with localized EFT have a better prognosis than patients with metastatic disease but no definitive biomarkers exist that can reliably predict outcome in either group. In other tumor types high-level expression of the polycomb gene BMI-1 has been shown to predict a worse outcome. In addition, BMI-1 over-expression is limited in these tumors to subpopulations of cells that also display properties of tumor-initiating cancer stem cells. We have previously reported that BMI-1 promotes EFT tumorigenicity. In the current study we have evaluated whether BMI-1 over-expression may be useful as a cancer stem cell or prognostic marker in EFT. Results: Using both RT-PCR (N=51) and immunohistochemical analysis (N=154) of archived tumor specimens we determined that BMI-1 is highly expressed by 80%-90% of EFT. In addition, in these BMI-1 positive tumors expression is diffuse and not limited to discrete subpopulations of cells. Conversely, in up to 20% of primary EFT BMI-1 positive tumor cells are rare to non-existent. In contrast to other tumor types, high levels of BMI-1 do not correlate with a worse clinical outcome in EFT. In fact, among patients with localized disease, high expression is associated with a trend towards improved overall survival (p=0.08). Analysis of BMI-1 positive versus negative samples failed to identify differences between the two groups in terms of age at presentation, anatomic site, stage, fusion type, or p16 or p53 mutation status. Significantly, however, whole genome expression studies revealed that the molecular profile of BMI-1 negative tumors is markedly different from BMI-1 positive tumors. In particular differentiation, cell cycle, and mRNA regulatory genes are highly differentially expressed between to two classes suggesting fundamental differences in molecular pathogenesis. Importantly, preliminary analysis suggests that loss of RB may compensate for BMI-1 over-expression in BMI-1 negative tumors. Conclusions: We have identified a previously unrecognized molecular subclass of EFT that is characterized by absence of BMI-1 expression. We propose that BMI-1 negative tumors have distinct molecular and/or cellular origins compared to the more common BMI-1 positive tumors.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2185.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO