Integrated DNA methylation analysis identifies topographical and tumoral biomarkers in pilocytic astrocytomas
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Manila Antonelli1,*, Antonio Fadda2,*, Eleonora Loi2, Loredana Moi2,3, Cesare Zavattari4, Pia Sulas5, Davide Gentilini6,7, Cinzia Cameli8, Elena Bacchelli8, Manuela Badiali3, Antonella Arcella9, Isabella Morra10, Felice Giangaspero1,9 and Patrizia Zavattari2
1Department of Radiological, Oncological and Anatomo-Pathological Sciences, University Sapienza of Rome, Rome, Italy
2Unit of Biology and Genetics, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
3Bone Marrow Transplantation Unit, Microcitemico Children's Hospital, Cagliari, Italy
4Independent Researcher, Machine Learning, Lucca, Italy
5Unit of Oncology and Molecular Pathology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
6Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
7Bioinformatics and Statistical Genomics Unit, Istituto Auxologico Italiano IRCCS, Cusano Milanino, Milan, Italy
8Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
9IRCCS Neuromed, Pozzilli, Italy
10Department of Pathology OIRM-S, Anna Hospital, A.O.U. City of Health and Science, Turin, Italy
*These authors contributed equally to this work
Patrizia Zavattari, email: [email protected]
Keywords: pilocytic astrocytomas; methylome alteration; topographic and tumor biomarkers; gene expression alteration; human methylation beadchips
Received: October 19, 2017 Accepted: January 31, 2018 Published: February 12, 2018
Pilocytic astrocytoma (PA) is the most common glioma in pediatric patients and occurs in different locations. Chromosomal alterations are mostly located at chromosome 7q34 comprising the BRAF oncogene with consequent activation of the mitogen-activated protein kinase pathway. Although genetic and epigenetic alterations characterizing PA from different localizations have been reported, the role of epigenetic alterations in PA development is still not clear. The aim of this study was to investigate whether distinctive methylation patterns may define biologically relevant groups of PAs. Integrated DNA methylation analysis was performed on 20 PAs and 4 normal brain samples by Illumina Infinium HumanMethylation27 BeadChips.
We identified distinct methylation profiles characterizing PAs from different locations (infratentorial vs supratentorial) and tumors with onset before and after 3 years of age. These results suggest that PA may be related to the specific brain site where the tumor arises from region-specific cells of origin. We identified and validated in silico the methylation alterations of some CpG islands. Furthermore, we evaluated the expression levels of selected differentially methylated genes and identified two biomarkers, one, IRX2, related to the tumor localization and the other, TOX2, as tumoral biomarker.
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