Karina Bezerra Salomão1,2,3, Gustavo Alencastro Veiga Cruzeiro4,5,6, Ricardo Bonfim-Silva5,6, Lenisa Geron4,5,6, Fernando Ramalho7,6, Fabiano Pinto Saggioro7,6, Luciano Neder Serafini7,6, Daniel Antunes Moreno5,6, Rosane Gomes de Paula Queiroz4,5,6, Simone Dos Santos Aguiar8, Izilda Cardinalli8, José Andres Yunes8, Silvia Regina Brandalise8, Maria Sol Brassesco6,9, Carlos Alberto Scrideli4,5,6, Luiz Gonzaga Tone4,5,6. 1. Department of Paediatrics, University of São Paulo, 3900, Bandeirantes Avenue, Ribeirão Preto, SP, 14049-900, Brazil. karina_slm@hotmail.com. 2. Department of Genetics, University of São Paulo, 3900, Bandeirantes Avenue, Ribeirão Preto, SP, 14049-900, Brazil. karina_slm@hotmail.com. 3. Ribeirão Preto School of Medicine, University of São Paulo, 3900, Bandeirantes Avenue, Ribeirão Preto, SP, 14049-900, Brazil. karina_slm@hotmail.com. 4. Department of Paediatrics, University of São Paulo, 3900, Bandeirantes Avenue, Ribeirão Preto, SP, 14049-900, Brazil. 5. Department of Genetics, University of São Paulo, 3900, Bandeirantes Avenue, Ribeirão Preto, SP, 14049-900, Brazil. 6. Ribeirão Preto School of Medicine, University of São Paulo, 3900, Bandeirantes Avenue, Ribeirão Preto, SP, 14049-900, Brazil. 7. Department of Pathology, University of São Paulo, 3900, Bandeirantes Avenue, Ribeirão Preto, SP, 14049-900, Brazil. 8. Boldrini Centre of Children, University of Campinas-UNICAMP, Campinas, SP, Brazil. 9. Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, 3900, Bandeirantes Avenue, Ribeirão Preto, SP, 14049-900, Brazil.
Abstract
INTRODUCTION: Medulloblastoma (MB) is an embryonal tumour that originates from genetic deregulation of cerebellar developmental pathways and is classified into 4 molecular subgroups: SHH, WNT, group 3, and group 4. Hydroxymethylation levels progressively increases during cerebellum development suggesting a possibility of deregulation in MB pathogenesis. The aim of this study was to investigate global hydroxymethylation levels and changes in TET and IDH gene expression in MB samples compared to control cerebellum samples. METHODS: The methods utilized were qRT-PCR for gene expression, dot-blot and immunohistochemistry for global hydroxymethylation levels and sequencing for the investigation of IDH mutations. RESULTS: Our results show that global hydroxymethylation level was decreased in MB, and low 5hmC level was associated with the presence of metastasis. TET1 expression levels were decreased in the WNT subgroup, while TET3 expression levels were decreased in the SHH subgroup. Reduced TET3 expression levels were associated with the presence of events such as relapse and death. Higher expression of IDH1 was observed in MB group 3 samples, whereas no mutations were detected in exon 4 of IDH1 and IDH2. CONCLUSION: These findings suggest that reduction of global hydroxymethylation levels, an epigenetic event, may be important for MB development and/or maintenance, representing a possible target in this tumour and indicating a possible interaction of TET and IDH genes with the developmental pathways specifically activated in the MB subgroups. These genes could be specific targets and markers for each subgroup.
INTRODUCTION:Medulloblastoma (MB) is an embryonal tumour that originates from genetic deregulation of cerebellar developmental pathways and is classified into 4 molecular subgroups: SHH, WNT, group 3, and group 4. Hydroxymethylation levels progressively increases during cerebellum development suggesting a possibility of deregulation in MB pathogenesis. The aim of this study was to investigate global hydroxymethylation levels and changes in TET and IDH gene expression in MB samples compared to control cerebellum samples. METHODS: The methods utilized were qRT-PCR for gene expression, dot-blot and immunohistochemistry for global hydroxymethylation levels and sequencing for the investigation of IDH mutations. RESULTS: Our results show that global hydroxymethylation level was decreased in MB, and low 5hmC level was associated with the presence of metastasis. TET1 expression levels were decreased in the WNT subgroup, while TET3 expression levels were decreased in the SHH subgroup. Reduced TET3 expression levels were associated with the presence of events such as relapse and death. Higher expression of IDH1 was observed in MB group 3 samples, whereas no mutations were detected in exon 4 of IDH1 and IDH2. CONCLUSION: These findings suggest that reduction of global hydroxymethylation levels, an epigenetic event, may be important for MB development and/or maintenance, representing a possible target in this tumour and indicating a possible interaction of TET and IDH genes with the developmental pathways specifically activated in the MB subgroups. These genes could be specific targets and markers for each subgroup.
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