Association of RASSF1A, DCR2, and CASP8 Methylation with Survival in Neuroblastoma: A Pooled Analysis Using Reconstructed Individual Patient Data

Abstract

Neuroblastoma (NB) is a heterogeneous tumor affecting children. It shows a wide spectrum of clinical outcomes; therefore, development of risk stratification is critical to provide optimum treatment. Since epigenetic alterations such as DNA methylation have emerged as an important feature of both development and progression in NB, in this study, we aimed to quantify the effect of methylation of three distinct genes (RASSF1A, DCR2, and CASP8) on overall survival in NB patients. We performed a systematic review using PubMed, Embase, and Cochrane libraries. Individual patient data was retrieved from extracted Kaplan-Meier curves. Data from studies was then merged, and analysis was done on the full data set. Seven studies met the inclusion criteria. Methylation of the three genes had worse overall survival than the unmethylated arms. Five-year survival for the methylated arm of RASSF1A, DCR2, and CASP8 was 63.19% (95% CI 56.55-70.60), 57.78% (95% CI 47.63-70.08), and 56.39% (95% CI 49.53-64.19), respectively, while for the unmethylated arm, it was 93.10% (95% CI 87.40-99.1), 84.84% (95% CI 80.04-89.92), and 83.68% (95% CI 80.28-87.22), respectively. In conclusion, our results indicate that in NB patients, RASSF1A, DCR2, and CASP8 methylation is associated with poor prognosis. Large prospective studies will be necessary to confirm definitive correlation between methylation of these genes and survival taking into account all other known risk factors. (PROSPERO registration number CRD42017082264).