Loss of caspase-8 expression does not correlate with MYCN amplification, aggressive disease, or prognosis in neuroblastoma

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 20; pp. 10016 - 10023
• Main Authors: FULDA, Simone, POREMBA, Christopher, BERWANGER, Bernd, HÄCKER, Sabine, EILERS, Martin, CHRISTIANSEN, Holger, HERO, Barbara, DEBATIN, Klaus-Michael
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.10.2006
• Subjects: Alstrom Syndrome; Antineoplastic agents; Biological and medical sciences; Blotting, Western; Caspase 8 - biosynthesis; Caspase 8 - genetics; Cell Line, Tumor; Disease Progression; DNA Methylation; Gene Amplification; Gene Expression Profiling; Genes, myc; Humans; Medical sciences; N-Myc Proto-Oncogene Protein; Neuroblastoma - enzymology; Neuroblastoma - genetics; Neuroblastoma - pathology; Neurology; Nuclear Proteins - biosynthesis; Nuclear Proteins - genetics; Oligonucleotide Array Sequence Analysis; Oncogene Proteins - biosynthesis; Oncogene Proteins - genetics; Pharmacology. Drug treatments; Tumors; Tumors of the nervous system. Phacomatoses; Peptidases; Nervous system diseases; Gene amplification; Prognosis; Enzyme; Cysteine endopeptidases; Hydrolases; Malignant tumor; Neuroblastoma; Autonomic neuropathy; Gene expression; High malignancy
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-05-4079

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.