Two independent epigenetic biomarkers predict survival in neuroblastoma

Abstract

BackgroundNeuroblastoma (NB) is the most common extracranial pediatric solid tumor with a highly variable clinical course, ranging from spontaneous regression to life-threatening disease. Survival rates for high-risk NB patients remain disappointingly low despite multimodal treatment. Thus, there is an urgent clinical need for additional biomarkers to improve risk stratification, treatment management, and survival rates in children with aggressive NB.ResultsUsing gene promoter methylation analysis in 48 neuroblastoma tumors with microarray technology, we found a strong association between survival and gene promoter hypermethylation (P = 0.036). Hypermethylation of 70 genes significantly differentiated high-risk survivor patients from those who died during follow-up time. Sixteen genes with relevant roles in cancer biology were further validated in an additional cohort of 83 neuroblastoma tumors by bisulfite pyrosequencing. High promoter methylation rates of these genes were found in patients with metastatic tumors (either stage metastatic (M) or metastatic special (MS)), 18 months or older at first diagnosis, MYCN amplification, relapsed, and dead. Notably, the degree of methylation of retinoblastoma 1 (RB1) and teratocarcinoma-derived growth factor 1 (TDGF1) predicts event-free and overall survival independently of the established risk factors. In addition, low RB1 mRNA expression levels associate with poor prognosis suggesting that promoter methylation could contribute to the transcriptional silencing of this gene in NB.ConclusionsWe found a new epigenetic signature predictive for NB patients’ outcome: the methylation status of RB1 and TDGF1 associate with poorer survival. This information is useful to assess prognosis and improve treatment selection.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0054-8) contains supplementary material, which is available to authorized users.

Methyl-CpG-binding domain sequencing reveals a prognostic methylation signature in neuroblastoma

“…In NB, several prognostic single-gene methylation biomarkers have been reported, e.g. promoter methylation of TNFRSF10D , CASP8 , ZMYND10 , RASSF1A , KRT19 , GNAS , HIST1H3C, RB1 and TDGF1 [ 6 - 11 ]. Furthermore, a CpG island methylator phenotype (CIMP), described as the aberrant and concordant methylation of multiple promoter CpG islands, has been shown to be of prognostic significance [ 12 - 16 ].…”

Tethered Oligonucleotide-Primed Sequencing, TOP-Seq: A High-Resolution Economical Approach for DNA Epigenome Profiling

“…We then tested whether the detected methylation events matched any group of genes that have been shown to be silenced by aberrant methylation in NB, e.g. CCND1/CCND2, RB1, RASSF1, ZMYND10, HIST1H3C, HOXD3, PCDHB cluster, etc (Caren et al, 2011; Decock et al, 2012; Yanez et al, 2015). Remarkably, hypermethylation of the promoter and/or intragenic CGIs was confirmed in all of the investigated NB marker genes in both NB cell types (genome-browser view of RASSF1 and ZMYND10 are shown in Fig.…”

Overall survival for neuroblastoma in South Africa between 2000 and 2014

“…Despite the use of high‐intensity treatment for HR disease, the outcomes for LR and HR disease are vastly dissimilar . Epigenetics is emerging as a factor influencing outcomes …”