Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN

Caspase 8 is a cysteine protease regulated in both a death-receptor-depende nt and -independent manner during apoptosis. Here, we report that the gene for caspase 8 is frequently inactivated in neuroblastoma, a childhood tumor of the peripheral nervous system. The gene is silenced through DNA methyla tion as well as through gene deletion. Complete inactivation of CASP8 occur red almost exclusively in neuroblastomas with amplification of the oncogene MYCN. Caspase 8-null neuroblastoma cells were resistant to death receptor- and doxorubicin-mediated apoptosis, deficits that were corrected by progra mmed expression of the enzyme. Thus, caspase 8 acts as a tumor suppressor i n neuroblastomas with amplification of MYCN.