Loss of caspase-8 protein expression correlates with unfavorable survival outcome in childhood medulloblastoma.

PURPOSE Escaping apoptosis is a hallmark of cancer. In medulloblastoma (MB) cell lines, resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis was recently shown to correlate with loss of caspase-8 mRNA expression, because of aberrant gene methylation (M. A. Grotzer et al., Oncogene, 19: 4604-4610, 2000). Loss of caspase-8 mRNA expression has been demonstrated in a subset of primary MB (T. J. Zuzak et al., Eur. J. Cancer, 38: 83-91, 2002). In this study, we analyzed primary MB samples to test whether loss of caspases correlates with survival outcome. EXPERIMENTAL DESIGN We used immunohistochemistry to analyze the protein expression of the key initiator caspase-8 and caspase-9 in paraffin-embedded tumor samples from 77 well characterized MB patients and compared the expression levels of caspase-8 and caspase-9 with apoptosis indices, clinical variables, and survival outcomes. RESULTS Weak expression of caspase-8 and caspase-9 was found in 16 and 24% of the MB samples evaluated, respectively. Weak expression of caspase-8 was an independent significant prognostic factor for unfavorable progression-free survival outcome and was more predictive than standard clinical factors. In contrast, caspase-9 expression was not a prognostic factor. Treatment of caspase-8-deficient MB cells with IFN-gamma resulted in dose-dependent restoration of caspase-8 mRNA and protein expression and restoration of tumor necrosis factor-related apoptosis-inducing ligand sensitivity. CONCLUSIONS Loss of initiator caspase-8 is associated with an unfavorable survival outcome. Restoration of caspase-8 (e.g., by treatment with IFN-gamma) might, therefore, represent a novel experimental therapy in childhood MB.