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The Over-Expression of E2F3 Might Serve as Prognostic Marker for Neuroblastoma Patients with Stage 4S Disease.

ABSTRACT: Stage 4S neuroblastoma is a childhood cancer occurring in infants (<12 months at diagnosis) with metastases limited to liver, skin, and bone marrow (<10%). It is associated with an excellent outcome, due to its notable ability to undergo spontaneous regression without any therapeutic intervention. However, a subgroup of patients is doomed to relapse and eventually to die in spite of aggressive therapies. Stage 4S neuroblastoma shows characteristic hypermethylation of genes involved in the telomere maintenance, indicating that the dysregulation of these genes might serve as prognostic marker. The retinoblastoma tumor suppressor protein (RB)-E2F transcription factors pathway is one of the critical tumor-suppressor/oncogene pathways involved in regulating telomerase expression. We have interrogated in silicopublic neuroblastoma databases for regulators involved in the RB-E2F pathway especially for E2F factors themselves, and we identified the E2F transcription factor 3 (E2F3) expression as a potential prognostic marker in stage 4S neuroblastoma. In order to confirm this finding, we screened 38 paraffin-embedded tissue samples stage 4S neuroblastoma for E2F3 protein expression using immunofluorescence, and we observed that augmented expression was strongly associated with impaired event-free survival. These results indicate that E2F3 expression might serve as prognostic marker in patients with stage 4S disease.

SUBMITTER: Parodi S

PROVIDER: S-EPMC7277942 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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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The Over-Expression of E2F3 Might Serve as Prognostic Marker for Neuroblastoma Patients with Stage 4S Disease.

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