Stage 4S neuroblastoma tumors show a characteristic DNA methylation portrait

Abstract

Stage 4S neuroblastoma (NB) is a special type of NB found in infants with metastases at diagnosis and is associated with an excellent outcome due to its remarkable capacity to undergo spontaneous regression. As genomics have not been able to explain this intriguing clinical presentation, we here aimed at profiling the DNA methylome of stage 4S NB to better understand this phenomenon. To this purpose, differential methylation analyses between International Neuroblastoma Staging System (INSS) stage 4S, stage 4 and stage 1/2 were performed, using methyl-CpG-binding domain (MBD) sequencing data of 14 stage 4S, 14 stage 4, and 13 stage 1/2 primary NB tumors (all MYCN nonamplified in order not to confound results). Stage 4S-specific hyper-and hypomethylated promoters were determined and further characterized for genomic localization and function by cytogenetic band enrichment, gene set enrichment, transcription factor target enrichment and differential RNA expression analyses. We show that specific chromosomal locations are enriched for stage 4S differentially methylated promoters and that stage 4S tumors show characteristic hypermethylation of specific subtelomeric promoters. Furthermore, genes involved in important oncogenic pathways, in neural crest development and differentiation, and in epigenetic processes are differentially methylated and expressed in stage 4S tumors. Based on these findings, we describe new biological mechanisms possibly contributing to the stage 4S-specific tumor biology and spontaneous regression. In conclusion, this study is the first to describe the highly characteristic stage 4S DNA methylome. These findings will open new avenues to further unravel the NB pathology in general and stage 4S disease specifically.

Hijacking of Embryonic Programs by Neural Crest-Derived Neuroblastoma: From Physiological Migration to Metastatic Dissemination

“…For example whole chromosomes gain or loss are similar between Stage 4 and Stage 4S (Bénard et al, 2008). Stage 4S specificities were finally identified from their molecular and epigenetic portraits (Bénard et al, 2008; Decock et al, 2016) opening new areas of research regarding the mechanisms contributing to their unique biology and propensity to regress spontaneously.…”

Monozygotic twins with neuroblastoma MS have a similar molecular profile: a case of twin-to-twin metastasis

“…Stage MS NBL is usually a sporadic disease with distinct clinical and molecular features that are different from neuroblastoma stage IV. 6,7 The occurrence of synchronous tumour in monozygotic twins may suggest the presence of a common genetic background as a predisposition factor for NBL genesis. Furthermore, fetoplacental metastasis is considered when monozygotic monochorionic twins have similar tumour pathology, but only one with identifiable primary tumour, presenting spontaneously, or shortly after.…”

Neuroblastoma and the epigenome

“…They observed hypermethylation in genes associated with subtelomeric regions. Moreover, the study showed hypermethylation of genes that are involved with neural crest development and differentiation in 4S subset compared to the tumors in stages 1, 2, or 4 [55]. Another critical gene involved in telomere maintenance is telomerase reverse transcriptase (TERT).…”