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

Stefano Parodi,Annalisa Pezzolo,Riccardo Haupt,Marzia Ognibene

doi:10.3390/diagnostics10050315

Stefano Parodi, Annalisa Pezzolo + Show 2 more

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https://doi.org/10.3390/diagnostics10050315

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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.

Highlights

Neuroblastoma (NB) is the most common extra-cranial solid tumor of childhood, and it is the main cause of death in children between 1 and 4 years [1,2]
We examined how RB1, telomerase reverse transcriptase (TERT), E2F1, E2F2, and E2F transcription factor 3 (E2F3) gene expressions linked to event-free survival (EFS) in stage 4S NB patients using gene expressions in the publicly available datasets consisting of primary tumor samples from three independent NB patient cohorts (Kocak-649 [26], Oberthuer-251 [27], and SEQC-RPM [28] datasets), downloaded from the R2: Genomic Analysis and Visualization Platform
We have identified that RB1 and TERT gene expressions had no association with EFS; low E2F1, E2F2 expression was slightly associated with a good EFS in all considered data sets, whereas high levels of E2F3 gene expression were associated to a poor survival in each considered data set

Summary

Introduction

Neuroblastoma (NB) is the most common extra-cranial solid tumor of childhood, and it is the main cause of death in children between 1 and 4 years [1,2]. NB is a heterogeneous disease with prognosis ranging from long-term survival to fatal outcome [4]. The clinical and biological parameters are used for therapeutic stratification of NB patients [5,6]. Stage 4S NB is a special type of NB established in infants with metastases limited to the liver, skin, and bone marrow (

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