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-γ 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-γ) might, therefore, represent a novel experimental therapy in childhood MB.