Molecular stratification of high-grade gliomas in children

The Research

Giangaspero F.

Brain tumours are the main cause of death due to malignant neoplasia in children. Childhood high-grade gliomas identified with the terms anaplastic astrocytoma and glioblastoma, are 15% of all pediatric brain tumours and have high morbidity and survival rate at three years is less than 20%.
Most of our knowledge concerns malignant gliomas in adults, in particular the glioblastoma (GBM) which is the most frequent primitive neoplasia of the central nervous system.
Recent studies on GBM gene expression in adults, helped to identify oncogenetic molecular events and to
stratify patients into prognostic groups. That is to say, the presence or not of some molecular alterations which enable us to predict the more or less aggressive clinical behaviour of these neoplasms. Childhood GBM are histologically similar to those in adults, but have different molecular features.
Our research projects are aimed at characterizing childhood malignant gliomas. Our results show that molecular mechanisms involved in gliomagenesis and progression are different from those in adults. We observed in particular that, differently from what happens in adults, in which mutation of the oncosuppressor gene p53 has no effect on the clinical trend, in childhood neoplasias TP53 gene mutations are associated to reduced survival.
We have also studied protein YKL-40 expression in child tumours that in adults is associated with a worse
response to radiotherapy and shorter overall survival. Our results showed that the expression of such protein in childhood malignant gliomas is very common but has no effect on prognosis.
Likewise, our studies as well as those of other groups show that IDH1 mutations, present in 80% of glial neoplasias in adults, are practically absent in childhood (Antonelli et al. Prognostic significance of histological grading, p53 status, YKL- 40 expression, and IDH1 mutations in pediatric high grade gliomas, Journal of Neuro-Oncology, in press). Another study we carried out aimed at assessing MGMT mutation in pediatric gliomas. When such gene is inactivated, chemotherapic agents act more effectively on tumour cells. Inactivation of this gene in adult gliomas has proven to be a favourable event with a considerable increase in survival. Our research on pediatric gliomas shows that gene MGMT inactivation is less frequent than in the adult and its correlation with response to treatment is not statistically significant (Buttarelli et al. Evaluation status and prognostic significance of MGMT in pediatric high grade gliomas, submitted).
The results of these studies together with those of others in literature strengthen the concept that, despite histological similarities, molecular mechanisms involved in the pathogenesis and neoplastic progression seem to be totally different in the two age groups. While knowledge of these tumours in adults is advanced, in childhood it is still very scarce. It should be pointed out that understanding such mechanisms is the first step towards the definition of new therapies based on specific molecular targets.
Our future research aims to study the expression of molecules involved in the activation of Ras and Akt molecular pathways which are involved in controlling cell growth, differentiation, and survival. Preliminary results highlight a different behaviour between tumors in which these pathways are activated and those in which activation is absent.

Prof. Felice Giangaspero
Laboratorio Neuropatologia
Policlinico Umberto I, Roma
Università Sapienza Roma
Viale del Policlinico, 155, 00197 Roma
Tel/fax: +390649979175
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Buttarelli FR, Massimino M, Antonelli M, Lauriola L, Nozza P, Donofrio V, Arcella A, Oliva MA, Di Rocco C, Giangaspero F.
Evaluation status and prognostic significance of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in pediatric high grade gliomas.
Childs Nerv Syst. 2010 Aug;26(8):1051-6. Epub 2010 Jun 16.

Antonelli M, Buttarelli FR, Arcella A, Nobusawa S, Donofrio V, Oghaki H, Giangaspero F.
Prognostic significance of histological grading, p53 status, YKL-40 expression, and IDH1 mutations in pediatric high-grade gliomas.
J Neurooncol. 2010 Sep;99(2):209-15. Epub 2010 Feb 21.

Manila Antonelli, Maura Massimino, Isabella Morra, Maria Luisa Garrè, Marina Paola Gardiman, Francesca Romana Buttarelli, Antonietta Arcella, Felice Giangaspero
Epression of pERK and pAKT in pediatric high grade astrocytomas: Correlation with YKL40 and prognostic significance.
Neuropathology 2011 Aug doi:10.1111/j.1440-1789.2011.01252.x.
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Manuela Badiali, Vincent Gleize, Sophie Paris, Loredana Moi, Selma Elhouadani, Antonietta Arcella, Roberta Morace, Manila Antonelli, Francesca Romana Buttarelli, Dominique Figarella- Branger, Young-Ho Kim, Hiroko Ohgaki, Karima Mokhtari, Marc Sanson, Felice Giangaspero
KIAA1549-BRAF Fusions and IDH Mutations Can Coexist in Diffuse Gliomas of Adults.
Brain Pathology (2012) ISSN 1015-6305.
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Manila Antonelli, Manuela Badiali, Francesca Romana Buttarelli, Caterina Baldi, V. Gleize, S. Paris, Loredana Moi, Paolo Nozza, Antonietta Arcella, Maura Massimino, Marc Sanson, Felice Giangaspero.
KIAA1549: BRAF fusion gene in pediatric brain tumors of different histogenesis.
Submitted to Brain Pathology (2013).
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