Epigenetic Analysis of Long-term Epilepsy-Associated Tumors by Methylation-Specific Multiplex Ligation-dependent Probe Amplification

Authors

  • Joana Jesus-Ribeiro Neurology Department, Leiria Hospital Center, Leiria, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR) and Center of Investigation on Environment, Genetics, and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal https://orcid.org/0000-0002-0197-6780
  • Ilda Patrícia Ribeiro Coimbra Institute for Clinical and Biomedical Research (iCBR) and Center of Investigation on Environment, Genetics, and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Laboratory of Cytogenetics and Genomics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal https://orcid.org/0000-0002-6096-8705
  • Luis Miguel Pires Coimbra Institute for Clinical and Biomedical Research (iCBR) and Center of Investigation on Environment, Genetics, and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Laboratory of Cytogenetics and Genomics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal https://orcid.org/0000-0003-0847-721X
  • Olinda Rebelo Neuropathology Laboratory, Neurology Department, Coimbra University Hospital Center, Coimbra, Portugal
  • Ricardo Pereira Neurosurgery Department, Coimbra University Hospital Center, Coimbra, Portugal https://orcid.org/0000-0002-6895-1318
  • Conceição Bento Epilepsy and Sleep Monitoring Unit, Neurology Department, Coimbra University Hospital Center, Coimbra, Portugal
  • Francisco Sales Epilepsy and Sleep Monitoring Unit, Neurology Department, Coimbra University Hospital Center, Coimbra, Portugal https://orcid.org/0000-0003-0834-066X
  • Isabel Santana Neurology Department, Coimbra University Hospital Center, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal https://orcid.org/0000-0002-8114-9434
  • António Freire Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Neurology Department, Luz Hospital, Coimbra, Portugal https://orcid.org/0000-0003-4995-6655
  • Joana Barbosa Melo Coimbra Institute for Clinical and Biomedical Research (iCBR) and Center of Investigation on Environment, Genetics, and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Laboratory of Cytogenetics and Genomics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

DOI:

https://doi.org/10.46531/sinapse/AO/220054/2023

Keywords:

Brain Neoplasms/diagnosis, Brain Neoplasms/genetics, DNA Methylation, Epilepsy, Gene Expression Profiling

Abstract

Introduction: Ganglioglioma and dysembryoplastic neuroepithelial tumor represent the most common neoplasms in the group of long-term epilepsy-associated tumors. Mapping of epigenetic alterations, particularly DNA methylation, has recently been shown to offer promising perspectives in brain tumors, identifying key genes that may serve as potential diagnostic biomarkers. We aim to perform a genetic and epigenetic analysis using long-term epilepsy-associated tumors’ tissue, to contribute to the identification of such biomarkers.
Methods: DNA copy number alterations and methylation status in genes relevant to tumorigeneses were analyzed by methylation-specific multiplex ligation-dependent probe amplification using fresh frozen postoperative tissue obtained from epilepsy surgery.
Results: From the six tumors included in the study (three gangliogliomas and three dysembryoplastic neuroepithelial tumors), one ganglioglioma harboring a BRAF:p.V600E mutation presented changes in methylation status. This particularly patient had a focal epilepsy with video-electroencephalogram (EEG) reveling an ictal pattern in the right occipito-parietal region. Brain magnetic resonance imaging revealed a right mesial temporal lesion. His seizure frequency increased despite antiepileptic treatment and two years later he underwent his first surgery. Two more surgeries were performed years later due to seizure recurrence associated to an increase of the residual tumor. Postsurgical Engel class is IIA at three years of follow-up. Copy number losses were detected in chromosomes 1p (TP73), 2p (MSH6), 3p (VHL), 10p (CREM), 11q (GSTP1), 12q (CHFR), 14q (MLH3), 16p (PYCARD), 17p (TP53), 17q (BRCA1) and 19p (STK11). Copy number gains were detected in chromosome 11p (CD44). The MGMT (58%) and CD44 (51%) genes were methylated.
Conclusion: A high number of chromosomal aberrations were identified in one ganglioglioma, among which deletions dominated, reinforcing the spectrum of chromosomal abnormalities previously described. We observed copy number gain and methylation in CD44, which contributes to cell-cell/cell-matrix interactions. The methylation of MGMT, involved in DNA repair, is concordant to other studies. Our data highlight the importance of unravel new chromosomal imbalances and the role of DNA methylation in theses tumors, which may provide more arguments in favor of an integrative histological and (epi)genetic classification.

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Published

2024-04-20

How to Cite

1.
Jesus-Ribeiro J, Ribeiro IP, Pires LM, Rebelo O, Pereira R, Bento C, et al. Epigenetic Analysis of Long-term Epilepsy-Associated Tumors by Methylation-Specific Multiplex Ligation-dependent Probe Amplification. Sinapse [Internet]. 2024 Apr. 20 [cited 2024 Nov. 21];22(4):160-8. Available from: https://sinapse.pt/index.php/journal/article/view/50

Issue

Vol. 22 No. 4 (2022): October - December

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Original Articles

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Copyright (c) 2024 Joana Jesus-Ribeiro, Ilda Patrícia Ribeiro, Luis Miguel Pires, Olinda Rebelo, Ricardo Pereira, Conceição Bento, Francisco Sales, Isabel Santana, António Freire, Joana Barbosa Melo

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