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Loss of Caspase-8 Expression Does Not Correlate with MYCN Amplification, Aggressive Disease, or Prognosis in Neuroblastoma

¹ University Children's Hospital, Ulm, Germany; ² Institute of Pathology, Heinrich-Heine-University, Düsseldorf, Germany; ³ Institute for Molecular Biology and Tumor Research; ⁴ University Children's Hospital, Marburg, Germany; and ⁵ Children's Hospital, Paediatric Oncology, University of Cologne, Cologne, Germany

Requests for reprints: Simone Fulda, University Children's Hospital, Eythstrasse 24, D-89075 Ulm, Germany. Phone: 49-731-5002-5980; Fax: 49-731-5002-6765; E-mail: simone.fulda{at}uniklinik-ulm.de.

Inactivation of caspase-8 because of aberrant gene methylation has been associated with amplification of the MYCN oncogene and aggressive disease in neuroblastoma, suggesting that caspase-8 may function as tumor suppressor. However, the prognostic effect of caspase-8 in neuroblastoma has remained obscure. Therefore, we investigated caspase-8 expression and its correlation with established prognostic markers and survival outcome in a large cohort of neuroblastoma patients. Here, we report that loss of caspase-8 protein expression occurs in the majority (75%) of neuroblastoma and is not restricted to advanced disease stages. Surprisingly, no correlation was observed between caspase-8 expression and MYCN amplification. Similarly, ectopic expression of MYCN or antisense-mediated down-regulation of MYCN had no effect on caspase-8 expression in neuroblastoma cell lines. In addition, caspase-8 expression did not correlate with other variables of high-risk disease (e.g., 1p36 aberrations, disease stage, age at diagnosis, or tumor histology). Most importantly, loss of caspase-8 protein had no effect on event-free or overall survival in the overall study population or in distinct subgroups of patients. By revealing no correlation between caspase-8 expression and MYCN amplification or other established variables of aggressive disease, our findings in a large cohort of neuroblastoma patients show that inactivation of caspase-8 is not a characteristic feature of aggressive neuroblastoma. Thus, our study provides novel insight into the biology of this tumor, which may have important clinical implications. (Cancer Res 2006; 66(20): 10016-23)

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