ADAR2 editing activity in newly diagnosed versus relapsed pediatric high-grade astrocytomas

Sara Tomaselli,Concezio Di Rocco,Luca Massimi,Libero Lauriola,Angela Mastronuzzi,Angela Gallo,Federica Galeano,Franco Locatelli

doi:10.1186/1471-2407-13-255

Abstract

BackgroundHigh-grade (WHO grade III and IV) astrocytomas are aggressive malignant brain tumors affecting humans with a high risk of recurrence in both children and adults. To date, limited information is available on the genetic and molecular alterations important in the onset and progression of pediatric high-grade astrocytomas and, even less, on the prognostic factors that influence long-term outcome in children with recurrence. A-to-I RNA editing is an essential post-transcriptional mechanism that can alter the nucleotide sequence of several RNAs and is mediated by the ADAR enzymes. ADAR2 editing activity is particularly important in mammalian brain and is impaired in both adult and pediatric high-grade astrocytomas. Moreover, we have recently shown that the recovered ADAR2 activity in high-grade astrocytomas inhibits in vivo tumor growth. The aim of the present study is to investigate whether changes may occur in ADAR2-mediated RNA editing profiles of relapsed high-grade astrocytomas compared to their respective specimens collected at diagnosis, in four pediatric patients.MethodsTotal RNAs extracted from all tumor samples and controls were tested for RNA editing levels (by direct sequencing on cDNA pools) and for ADAR2 mRNA expression (by qRT-PCR).ResultsA significant loss of ADAR2-editing activity was observed in the newly diagnosed and recurrent astrocytomas in comparison to normal brain. Surprisingly, we found a substantial rescue of ADAR2 editing activity in the relapsed tumor of the only patient showing prolonged survival.ConclusionsHigh-grade astrocytomas display a generalized loss of ADAR2-mediated RNA editing at both diagnosis and relapse. However, a peculiar Case, in complete remission of disease, displayed a total rescue of RNA editing at relapse, intriguingly suggesting ADAR2 activity/expression as a possible marker for long-term survival of patients with high-grade astrocytomas.

Highlights

High-grade (WHO grade III and IV) astrocytomas are aggressive malignant brain tumors affecting humans with a high risk of recurrence in both children and adults
RNA editing in newly diagnosed versus recurrent pediatric high-grade astrocytomas It is emerging the idea that differences in molecular characteristics can be present in newly diagnosed versus recurrent malignant high-grade astrocytomas [2,24]
We focused on recoding editing events of transcripts that translate into brain membrane receptors or ion channels, such as the receptor subunit of the AMPA channel (GluR-B), the receptor subunits of the Kainate channel (GluR-5 and GluR-6) and the potassium channel (Kv1.1), because these sites are mainly, if not exclusively, edited by ADAR2 enzyme [12]

Summary

Introduction

High-grade (WHO grade III and IV) astrocytomas are aggressive malignant brain tumors affecting humans with a high risk of recurrence in both children and adults. To date, limited information is available on the genetic and molecular alterations important in the onset and progression of pediatric high-grade astrocytomas and, even less, on the prognostic factors that influence long-term outcome in children with recurrence. ADAR2 editing activity is important in mammalian brain and is impaired in both adult and pediatric high-grade astrocytomas. To date limited information is available on the genetic and molecular alterations in pediatric patients important for the onset and progression of high-grade astrocytomas and even less is known about the prognostic factors that influence the long-term outcome in children with recurrence [5,6,7]. Adar1−/− and Adar2−/− knockout mice die at embryonic or post-natal stages, respectively, indicating that these enzymes are essential for survival in mammals [12,13]

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