Stronger Prognostic Power of the CpG Island Methylator Phenotype than Methylation of Individual Genes in Neuroblastomas

Objective: The CpG island methylator phenotype is strongly associated with poor survival in neuroblastomas. Neuroblastomas with the CpG island methylator phenotype include almost all neuroblastomas with MYCN amplification, and, even among neuroblastomas without MYCN amplification, have worse prognosis. At the same time, methylation of individual tumorsuppressor genes is also reported to be associated with poor survival. The purpose of this study was to compare the prognostic power of the CpG island methylator phenotype with that of methylation of individual genes. Methods: Methylation-specific polymerase chain reaction was performed for five individual genes (CASP8, EMP3, HOXA9, NR1I2 and CD44) in 140 Japanese and 152 German neuroblastomas. Kaplan‐Meier analysis and log-rank tests were conducted to compare the survival between groups defined by methylation status. Results: Among the five individual genes, only CASP8 methylation had a significant association with poor overall survival both in Japanese (hazard ratio ¼ 3.1; 95% confidence interval ¼ 1.5‐6.4; P ¼ 0.002) and German (hazard ratio ¼ 4.8; 95% confidence interval ¼ 2.1‐11; P ¼ 0.0002) neuroblastomas. HOXA9 and NR1I2 methylation were associated with poor survival only in German neuroblastomas. On the other hand, the CpG island methylator phenotype had a strong and consistent association in Japanese (hazard ratio ¼ 22; 95% confidence interval ¼ 5.3‐93; P ¼ 1.5 10 ‐5 ) and German (hazard ratio ¼ 9.5; 95% confidence interval ¼ 3.2‐28; P ¼ 4.7 10 ‐5 ) neuroblastomas. Conclusion: The CpG island methylator phenotype is likely to have stronger prognostic power than methylation of individual genes in neuroblastomas.