title: Loss of caspase-8 expression does not correlate with MYCN amplification, aggressive disease, or prognosis in neuroblastoma.
abstract: 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.
authors.affiliation: University Children's Hospital, Ulm, Germany. simone.fulda@uniklinik-ulm.de
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
authors.forename: Christopher
authors.initials: C
authors.lastname: Poremba
authors.forename: Bernd
authors.initials: B
authors.lastname: Berwanger
authors.forename: Sabine
authors.initials: S
authors.lastname: Häcker
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
authors.forename: Holger
authors.initials: H
authors.lastname: Christiansen
authors.forename: Barbara
authors.initials: B
authors.lastname: Hero
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
mesh_terms: 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
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D053181:Caspase 8