Loss of caspase-8 expression does not correlate with MYCN amplification, aggressive disease, or prognosis in neuroblastoma.
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.
Fulda
Simone
S
University Children's Hospital, Ulm, Germany. simone.fulda@uniklinik-ulm.de
Poremba
Christopher
C
Berwanger
Bernd
B
Häcker
Sabine
S
Eilers
Martin
M
Christiansen
Holger
H
Hero
Barbara
B
Debatin
Klaus-Michael
KM
D056769:Alstrom Syndrome; D015153:Blotting, Western; D053181:Caspase 8 / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation; D018450:Disease Progression; D005784:Gene Amplification; D020869:Gene Expression Profiling; D016259:Genes, myc; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics
C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D053181:Caspase 8