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Neuroblastoma of undifferentiated subtype, prognostic significance of prominent nucleolar formation, and MYC/MYCN protein expression: a report from the Children's Oncology Group.

ABSTRACT: This study sought to investigate biological/clinicopathological characteristics of neuroblastoma, undifferentiated subtype (NBUD).This study examined 157 NBUD cases filed at the Children's Oncology Group Neuroblastoma Pathology Reference Laboratory, and survival rates of the patients were analyzed with known prognostic factors. Immunostainings for MYCN and MYC protein were performed on 68 tumors.NBUD cases had a poor prognosis (48.4% ± 5.0% 3-year event-free survival [EFS]; 56.5% ± 5.0% overall survival [OS]), and were often associated with high mitosis-karyorrhexis index (MKI, 65%), prominent nucleoli (PN, 83%), ? 18 months of age (75%), MYCN amplification (MYCN-A, 83%), diploid pattern (63%), and 1pLOH (loss of heterozygosity (72%). However, these prognostic indicators, except for MYCN status, had no significant impact on survival. Surprisingly, EFS for patients with MYCN-A tumors (53.4% ± 5.6%) was significantly better (P=.0248) than for patients with MYCN-nonamplified (MYCN-NA) tumors (31.7% ± 11.7%), with MYCN-NA and PN (+) tumors having the worst prognosis (9.3%? ± 8.8%, P=.0045). Immunohistochemically, MYCN expression was found in 42 of 48 MYCN-A tumors. In contrast, MYC expression was almost exclusively found in the MYCN-NA tumors (9 of 20) especially when they had PN (8 of 11). Those patients with only MYC-positive tumors had the worst EFS (N=8, 12.5% ± 11.7%) compared with only MYCN-positive (N=39, 49.9% ± 17.7%) and both negative tumors (N=15, 70.0% ± 17.1%) (P=?.0029). High MKI was often found in only MYCN-positive (30 of 38) but rarely in only MYC-positive (2 of 8) tumors.NBUD represents a unique subtype of neuroblastoma associated with a poor prognosis. In this subtype, MYC protein expression may be a new prognostic factor indicating more aggressive clinical behavior than MYCN amplification and subsequent MYCN protein expression.

SUBMITTER: Wang LL

PROVIDER: S-EPMC4554323 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Neuroblastoma of undifferentiated subtype, prognostic significance of prominent nucleolar formation, and MYC/MYCN protein expression: a report from the Children's Oncology Group.

Wang Larry L LL Suganuma Rie R Ikegaki Naohiko N Tang Xao X Naranjo Arlene A McGrady Patrick P London Wendy B WB Hogarty Michael D MD Gastier-Foster Julie M JM Look A Thomas AT Park Julie R JR Maris John M JM Cohn Susan L SL Seeger Robert C RC Shimada Hiroyuki H

Cancer 20130730 20

<h4>Background</h4>This study sought to investigate biological/clinicopathological characteristics of neuroblastoma, undifferentiated subtype (NBUD).<h4>Methods</h4>This study examined 157 NBUD cases filed at the Children's Oncology Group Neuroblastoma Pathology Reference Laboratory, and survival rates of the patients were analyzed with known prognostic factors. Immunostainings for MYCN and MYC protein were performed on 68 tumors.<h4>Results</h4>NBUD cases had a poor prognosis (48.4% ± 5.0% 3-ye ...[more]

PMID: 23901000

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Project description:BackgroundNeuroblastoma patients with MYCN amplification are associated with poor prognosis. However, the prognostic relevance of MYCN associated genes in neuroblastoma is unclear.MethodsThe expression profiles of MYCN associated genes were identified from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) datasets. Enriched transcription factors and signaling pathways were determined using gene set enrichment analysis (GSEA). Kaplan-Meier plotter was used to identify the prognostic relevance of MYCN associated genes. Multivariate cox regression and Spearman's correlation were used to determine the correlation coefficients of MYCN associated genes.ResultsIn TARGET and GSE85047 datasets, neuroblastoma patients with MYCN amplification were associated with worse prognosis. Transcription factor MYC was positively associated with MYCN amplification in GSEA assay. We identified 13 MYC target genes which were increased in neuroblastoma patients with MYCN amplification in TARGET, GSE19274 and GSE85047 datasets. Moreover, six out of the 13 MYC target genes ARMC6, DCTPP1, EIF4G1, ELOVL6, FBL and PRMT1 were associated with adverse prognosis in TARGET and GSE85047 datasets. Transcription factor E2F1 was up-regulated by MYCN amplification and associated with the poor prognosis of neuroblastoma. Furthermore, RPS19 in ribosome signaling pathway was also associated with MYCN amplification and correlated with the poor prognosis of neuroblastoma. At last, we showed that most of MYCN target genes were correlated with each other. However, EIF4G1 was an independent prognostic marker. And the prognostic effects of the combination of MYCN amplification and EIF4G1 expression were more significant than MYCN or EIF4G1 alone.ConclusionsMYCN target genes ARMC6, DCTPP1, EIF4G1, ELOVL6, FBL, PRMT1, E2F1 and RPS19 had significant prognostic effects in pediatric neuroblastoma. And neuroblastoma patients without MYCN amplification and low EIF4G1 expression had best prognosis.

Project description:Targeting glutamine metabolism has emerged as a potential therapeutic strategy for Myc overexpressing cancer cells. Myc proteins contribute to an aggressive neuroblastoma phenotype. Radiotherapy is one of the treatment modalities for high-risk neuroblastoma patients. Herein, we investigated the effect of glutamine deprivation in combination with irradiation in neuroblastoma cells representative of high-risk disease and studied the role of Myc member interplay in regulating neuroblastoma cell radioresistance. Methods: Cell proliferation and viability assays were used to establish the effect of glutamine deprivation in neuroblastoma cells expressing c-Myc or MycN. Gene silencing and overexpression were used to modulate the expression of Myc genes to determine their role in neuroblastoma radioresistance. qPCR and western blot investigated interplay between expression of Myc members. The impact of glutamine deprivation on cell response following irradiation was explored using a radiobiological 3D colony assay. DNA repair gene pathways as well as CSC-related genes were studied by qPCR array. Reactive Oxygen Species (ROS) and glutathione (GSH) levels were detected by fluorescence and luminescence probes respectively. Cancer-stem cell (CSC) properties were investigated by sphere-forming assay and flow cytometry to quantify CSC markers. Expression of DNA repair genes and CSC-related genes was analysed by mining publicly available patient datasets. Results: Our results showed that glutamine deprivation decreased neuroblastoma cell proliferation and viability and modulated Myc member expression. We then demonstrated for the first time that combined glutamine deprivation with irradiation led to a selective radioresistance of MYCN-amplified neuroblastoma cells. By exploring the underlying mechanism of neuroblastoma radioresistance properties, our results highlight interplay between c-Myc and MycN expression suggesting compensatory mechanisms in Myc proteins leading to radioresistance in MYCN-amplified cells. This result was associated with the ability of MYCN-amplified cells to dysregulate the DNA repair gene pathway, maintain GSH and ROS levels and to increase the CSC-like population and properties. Conversely, glutamine deprivation led to radiosensitization in non-MYCN amplified cell lines through a disruption of the cell redox balance and a trend to decrease in the CSC-like populations. Mining publicly available gene expression dataset obtained from pediatric neuroblastoma patients, we identified a correlation pattern between Myc members and CSC-related genes as well as a specific group of DNA repair gene pathways. Conclusions: This study demonstrated that MycN and c-Myc tightly cooperate in regulation of the neuroblastoma CSC phenotypes and radioresistance upon glutamine deprivation. Pharmacologically, strategies targeting glutamine metabolism may prove beneficial in Myc-driven tumors. Consideration of MycN/c-Myc status in selecting neuroblastoma patients for glutamine metabolism treatment will be important to avoid potential radioresistance.

Dataset Information

Neuroblastoma of undifferentiated subtype, prognostic significance of prominent nucleolar formation, and MYC/MYCN protein expression: a report from the Children's Oncology Group.

Publications

Neuroblastoma of undifferentiated subtype, prognostic significance of prominent nucleolar formation, and MYC/MYCN protein expression: a report from the Children's Oncology Group.

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