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High-resolution, genome-wide analysis of human metastatic neuroblastoma samples by array-Comparative Genomic Hybridization (aCGH)

ABSTRACT: Less than 30% of children with high-risk (HR) metastatic neuroblastoma (NB) show a long survival (Pearson 2000). In order to identify novel molecular prognostic markers useful to better predict patients’ relapse risk estimation, we performed genome- and/or transcriptome-wide analyses of 129 stage 4 HR-NBs. This is the largest study for this NB subtype. Children older than 1 year of age at diagnosis were categorized as “short-survivors” (dead of disease within 5 years from diagnosis) and “long-survivors” (alive with an overall survival time > 5 years). A significant correlation of patient survival with the presence of small number of segmental copy number aberrations (CNA < 3) was observed. Thus, within the group of stage 4 HR-NBs, we identified a specific subgroup of patients (those with highest number of CNA) that have a higher risk of progression/recurrence. The complex genomic pattern is an independent prognostic marker, since MYCN oncogene amplification only affects the predictive value of single CNA (i.e., 1p loss, 17q gain). Integrative analysis of genomic and expression signatures demonstrated that fatal outcome is associated with loss of cell cycle control and with progression of tumor due to deregulation of Rho GTPase signaling and genes related to cell motility. Tumors with MYCN amplification showed a lower chromosome instability compared to MYCN-single copy NBs (P=0.0008), dominated by 17q gain and 1p loss. Moreover, our results suggest that the MYCN amplification mainly drives the disruption of neuronal differentiation and the reduction of cell adhesion process involved in tumor invasion and metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE35953 | GEO | 2012/10/05

SECONDARY ACCESSION(S): PRJNA151989

REPOSITORIES: GEO

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Project description:Less than 30% of children with high-risk (HR) metastatic neuroblastoma (NB) show a long survival (Pearson 2000). In order to identify novel molecular prognostic markers useful to better predict patientsM-bM-^@M-^Y relapse risk estimation, we performed genome- and/or transcriptome-wide analyses of 129 stage 4 HR-NBs. This is the largest study for this NB subtype. Children older than 1 year of age at diagnosis were categorized as M-bM-^@M-^\short-survivorsM-bM-^@M-^] (dead of disease within 5 years from diagnosis) and M-bM-^@M-^\long-survivorsM-bM-^@M-^] (alive with an overall survival time > 5 years). A significant correlation of patient survival with the presence of small number of segmental copy number aberrations (CNA < 3) was observed. Thus, within the group of stage 4 HR-NBs, we identified a specific subgroup of patients (those with highest number of CNA) that have a higher risk of progression/recurrence. The complex genomic pattern is an independent prognostic marker, since MYCN oncogene amplification only affects the predictive value of single CNA (i.e., 1p loss, 17q gain). Integrative analysis of genomic and expression signatures demonstrated that fatal outcome is associated with loss of cell cycle control and with progression of tumor due to deregulation of Rho GTPase signaling and genes related to cell motility. Tumors with MYCN amplification showed a lower chromosome instability compared to MYCN-single copy NBs (P=0.0008), dominated by 17q gain and 1p loss. Moreover, our results suggest that the MYCN amplification mainly drives the disruption of neuronal differentiation and the reduction of cell adhesion process involved in tumor invasion and metastasis. For array-CGH profiling, we analyzed 91 samples of metastatic neuroblastomas. All patients were classified as stage 4 and they were older than 1 year of age at time of diagnosis. Regarding the clinical course, 46 were short-survivors (dead of disease within 60 months from diagnosis. Deaths due to toxicity were censored) and 45 were long-survivors (alive with an overall survival time > 60 months). This submission consists of 22 new samples and 69 other cases previously deposited in GEO under Series accessions GSE14109 and GSE25771.

Project description:Neuroblastoma (NB) is an embryonal tumor with various clinical presentations and behaviors. Several genomic alterations has been well-studied in NB, among which genomic amplification of MYCN oncogene, is a strong prognostic biomarker with worsens outcome. Long noncoding RNAs (lncRNAs), constitute major proportion of the cellular transcripts with no coding capacity. One of their function is to guide transcription factors to the target genes and facilitate gene expression. However, relative contribution of lncRNA and MYCN to the advanced NB has remained unclear. Herein, by applying a network-based integrative analysis on MYCN amplified and MYCN nonamplified lncRNA expression profile from both RNA-seq and microarray platform, we identified lncRNA, SNHG1 to be differentially expressed and strongly correlated with MYCN in MYCN-amplified NB. The expression of SNHG1 was validated by RT-qPCR in NB cell lines. Survival analysis revealed that higher expression of SNHG1 significantly associates with poor patient survival. Moreover, knockdown of MYCN in MYCN-amplified NB cell lines inhibited SNHG1 expression. Furthermore, to unravel the role of SNHG1 in NB, we extracted SNHG1-interacting proteins by RNA-protein pull down assay coupled with doi:10.6342/NTU201701980 ! ! VI liquid chromatography-tandem mass spectrometry (LC-MS/MS). We identified 27 SNHG1-interacting proteins in common from three NB cell lines. However, only three SNHG1-interacting proteins, MATR3, YBX1 and HHRNPL have binding site detected by DeepBind motif analysis. Western blot confirms interaction of MATR3 with SNHG1. Additionally, we further validated the direct interaction between MATR3 and SNHG1 by RNA-immunoprecipation (IP). MATR3 is known to be involved in RNA transport and stabilization. Therefore, we proposed that MATR3 after interacting with SNHG1 might help in SNHG1 transcription and stabilization. In conclusion, our study unveils that SNHG1 could be a prognostic marker for high-risk NB and possibly stabilized by MATR3. Our results might provide future directions for the development of therapeutic strategies against high-risk NB.

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High-resolution, genome-wide analysis of human metastatic neuroblastoma samples by array-Comparative Genomic Hybridization (aCGH)

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