Dataset Information

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 non-amplified 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.

SUBMITTER: Decock A

PROVIDER: S-EPMC5094630 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Stage 4S neuroblastoma tumors show a characteristic DNA methylation portrait.

Decock Anneleen A Ongenaert Maté M De Wilde Bram B Brichard Bénédicte B Noguera Rosa R Speleman Frank F Vandesompele Jo J

Epigenetics 20161001 10

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) stag ...[more]

PMID: 27599161

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Project description:BackgroundAberrant DNA methylation of regulatory genes has frequently been found in human breast cancers and correlated to clinical outcome. In the present study we investigate stage specific changes in the DNA methylation patterns in order to identify valuable markers to understand how these changes affect breast cancer progression.MethodsQuantitative DNA methylation analyses of 12 candidate genes ABCB1, BRCCA1, CDKN2A, ESR1, GSTP1, IGF2, MGMT, HMLH1, PPP2R2B, PTEN, RASSF1A and FOXC1 was performed by pyrosequencing a series of 238 breast cancer tissue samples from DCIS to invasive tumors stage I to IV.ResultsSignificant differences in methylation levels between the DCIS and invasive stage II tumors were observed for six genes RASSF1A, CDKN2A, MGMT, ABCB1, GSTP1 and FOXC1. RASSF1A, ABCB1 and GSTP1 showed significantly higher methylation levels in late stage compared to the early stage breast carcinoma. Z-score analysis revealed significantly lower methylation levels in DCIS and stage I tumors compared with stage II, III and IV tumors. Methylation levels of PTEN, PPP2R2B, FOXC1, ABCB1 and BRCA1 were lower in tumors harboring TP53 mutations then in tumors with wild type TP53. Z-score analysis showed that TP53 mutated tumors had significantly lower overall methylation levels compared to tumors with wild type TP53. Methylation levels of RASSF1A, PPP2R2B, GSTP1 and FOXC1 were higher in ER positive vs. ER negative tumors and methylation levels of PTEN and CDKN2A were higher in HER2 positive vs. HER2 negative tumors. Z-score analysis also showed that HER2 positive tumors had significantly higher z-scores of methylation compared to the HER2 negative tumors. Univariate survival analysis identifies methylation status of PPP2R2B as significant predictor of overall survival and breast cancer specific survival.ConclusionsIn the present study we report that the level of aberrant DNA methylation is higher in late stage compared with early stage of invasive breast cancers and DCIS for genes mentioned above.

Project description:Background: The spontaneous regression of neuroblastoma (NB) is most prevalent and well-documented in stage 4s NB patients. However, whether autophagy plays roles in the spontaneous regression of NB is unknown. Objective: This study aimed to identify autophagy-related genes (ARGs) and autophagy-related long non-coding RNAs (lncRNAs) differentially expressed in stage 4 and stage 4s NB and to build prognostic risk signatures on the basis of the ARGs and autophagy-related lncRNAs. Methods: One RNA-sequence (RNA-Seq) dataset (TARGET NBL, n = 153) was utilized as discovery cohort, and two microarray datasets (n = 498 and n = 223) were used as validation cohorts. Differentially expressed ARGs were identified by comparing stage 4s and stage 4 NB samples. An ARG signature risk score and an autophagy-related lncRNA signature risk score were constructed. The receiver operating characteristic (ROC) curve analyses were used to evaluate the survival prediction ability of the two signatures. Gene function annotation and Gene Set Enrichment Analysis (GSEA) were performed to clarify the autophagic biological processes enriched in different risk groups. Results: Nine ARGs were integrated into the ARG signature. Patients in the high-risk group of the ARG signature had significantly poorer overall survival (OS) than patients in the low-risk group. The ROC curves analyses revealed that the ARG signature performed very well in predicting OS [5-year area under the curve (AUC) = 0.81]. Seven autophagy-related lncRNAs were integrated into the autophagy-related lncRNA signature. Patients in the high-risk group of the lncRNA signature had significantly poorer OS than patients in the low-risk group. The ROC curve analyses also revealed that the lncRNA signature performed well in predicting OS (5-year AUC = 0.77). Both the ARG signature and lncRNA signature are independent with other clinical risk factors in the multivariate Cox regression survival analyses. GSEAs revealed that autophagy-related biological processes are enriched in low-risk groups. Conclusions: Autophagy-related genes and lncRNAs are differentially expressed between stage 4 and stage 4s NB. The ARG signature and autophagy-related lncRNA signature successfully stratified NB patients into two risk groups. Autophagy-related biological processes are highly enriched in low-risk NB groups.

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Stage 4S neuroblastoma tumors show a characteristic DNA methylation portrait.

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Stage 4S neuroblastoma tumors show a characteristic DNA methylation portrait.

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