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Methylation of CASP8, DCR2, and HIN-1 in Neuroblastoma Is Associated with Poor Outcome

Authors' Affiliations: ¹ The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine; ² Institute for Molecular Pediatric Sciences, University of Chicago, Chicago, Illinois; and ³ Children's Oncology Group (COG) Statistics and Data Center, University of Florida, Gainesville, Florida

Requests for reprints: Susan L. Cohn, Institute for Molecular Pediatric Sciences, University of Chicago, 5841 Maryland Avenue, MC 4060, Room N114, Chicago, IL 60637. Phone: 773-702-2571; Fax: 773-834-1329; E-mail: scohn{at}peds.bsd.uchicago.edu.

Purpose: Epigenetic aberrations have been shown to play an important role in the pathogenesis of most cancers. To investigate the clinical significance of epigenetic changes in neuroblastoma, we evaluated the relationship between clinicopathologic variables and the pattern of gene methylation in neuroblastoma cell lines and tumors.

Experimental Design: Methylation-specific PCR was used to evaluate the gene methylation status of 19 genes in 14 neuroblastoma cell lines and 8 genes in 70 primary neuroblastoma tumors. Associations between gene methylation, established prognostic factors, and outcome were evaluated. Log-rank tests were used to identify the number of methylated genes that was most predictive of overall survival.

Results: Epigenetic changes were detected in the neuroblastoma cell lines and primary tumors, although the pattern of methylation varied. Eight of the 19 genes analyzed were methylated in >70% of the cell lines. Epigenetic changes of four genes were detected in only small numbers of cell lines. None of the cell lines had methylation of the other seven genes analyzed. In primary neuroblastoma tumors, high-risk disease and poor outcome were associated with methylation of DCR2, CASP8, and HIN-1 individually. Although methylation of the other five individual genes was not predictive of poor outcome, a trend toward decreased survival was seen in patients with a methylation phenotype, defined as 4 methylated genes (P = 0.055).

Conclusion: Our study indicates that clinically aggressive neuroblastoma tumors have aberrant methylation of multiple genes and provides a rationale for exploring treatment strategies that include demethylating agents.

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