© Copyright 2009 by the Society for Neuro-Oncology
Received July 23, 2008
Accepted December 8, 2008
Basic and Translational Investigations
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Analysis of microsatellite instability in medulloblastoma
Marta Viana-Pereira 1,
Inês Almeida 1,
Sónia Sousa 2,
Bethânia Mahler-Araújo 3,
Raquel Seruca 2,
José Pimentel 4,
Rui Manuel Reis 5*
1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal
2 Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
3 Histopathology Department, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK
4 Laboratory of Neuropathology, Hospital de Santa Maria, Institute of Molecular Medicine, Lisbon, Portugal
5 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
* To whom correspondence should be addressed. E-mail: rreis{at}ecsaude.uminho.pt.
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Abstract |
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Medulloblastoma is the most common malignant brain tumor in children. The presence of microsatellite instability (MSI) in brain tumors, particularly medulloblastomas, has not been properly addressed. The aim of the present study was to evaluate the role of MSI in medulloblastomas’ carcinogenesis. MSI status was determined in 36 patients using a pentaplex PCR of quasimonomorphic markers (NR27, NR21, NR24, BAT25 and BAT26). Methylation status of mismatch repair (MMR) genes was achieved by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). In addition, MSH6 expression was determined by immunohistochemistry. Mutations of ten MSI target genes (TCF4, XRCC2, MBD4, MRE11, ATR, MSH3, TGFBR2, RAD50, MSH6, and BAX) were studied by pentaplex PCR followed by analysis with the GeneScan 3.7 software. Mutation analysis of hot spot regions of 
-catenin (CTNNB1) and BRAF oncogenes was performed by PCR-SSCP analysis followed by direct sequencing. Among the 36 tumors, we found four (11%) cases with instability, one with MSI-H and three with MSI-L. Methylation analysis of MMR genes, on cases presenting shifts on the MSI markers, revealed mild hypermethylation of MSH6 in 75% of the cases, yet, MSH6 was expressed in all the tumors. The MSI-target genes MBD4 and MRE11 were mutated in two different tumors. No CTNNB1 or BRAF mutations were found. This study is the most comprehensive analysis of MSI in medulloblastomas. We observed the presence of MSI together with mutations of MSI target genes in a small fraction of cases, suggesting a new genetic pathway for role in medulloblastomas’ development.
Key Words:
medulloblastoma, microsatellite instability, mismatch repair, target genes
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