Microsatellite Instability in Pediatric High Grade Glioma Is Associated with Genomic Profile and Differential Target Gene Inactivation, PLoS One, Vol. 6(5), e20588 Microsatellite Instability in Pediatric High Grade Glioma Is Associated with Genomic Profile and Differential Target Gene Inactivation

High grade gliomas (HGG) are one of the leading causes of cancer-related deaths in children, and there is increasing evidence that pediatric HGG may harbor distinct molecular characteristics compared to adult tumors. We have sought to clarify the role of microsatellite instability (MSI) in pediatric versus adult HGG. MSI status was determined in 144 patients (71 pediatric and 73 adults) using a well established panel of five quasimonomorphic mononucleotide repeat markers. Expression of MLH1, MSH2, MSH6 and PMS2 was determined by immunohistochemistry, MLH1 was assessed for mutations by direct sequencing and promoter methylation using MS-PCR. DNA copy number profiles were derived using array CGH, and mutations in eighteen MSI target genes studied by multiplex PCR and genotyping. MSI was found in 14/71 (19.7%) pediatric cases, significantly more than observed in adults (5/73, 6.8%; p = 0.02, Chi-square test). MLH1 expression was downregulated in 10/13 cases, however no mutations or promoter methylation were found. MSH6 was absent in one pediatric MSI-High tumor, consistent with an inherited mismatch repair deficiency associated with germline MSH6 mutation. MSI was classed as Type A, and associated with a remarkably stable genomic profile. Of the eighteen classic MSI target genes, we identified mutations only in MSH6 and DNAPKcs and described a polymorphism in MRE11 without apparent functional consequences in DNA double strand break detection and repair. This study thus provides evidence for a potential novel molecular pathway in a proportion of gliomas associated with the presence of MSI. Citation: Viana-Pereira M, Lee A, Popov S, Bax DA, Al-Sarraj S, et al. (2011) Microsatellite Instability in Pediatric High Grade Glioma Is Associated with Genomic Profile and Differential Target Gene Inactivation. PLoS ONE 6(5): e20588. doi:10.1371/journal.pone.0020588 Editor: Kerstin Borgmann, University Medical Center Hamburg-Eppendorf, Germany Received November 10, 2010; Accepted May 6, 2011; Published May 26, 2011 Copyright: 2011 Viana-Pereira et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors acknowledge the British Council and the Portuguese Council of Rectors, Treaty of Windsor Anglo-Portuguese Joint Research Programme (R.M. Reis, C. Jones). M. Viana-Pereira is funded by a PhD fellowship ‘[SFRH/BD/29145/2006]’ of Fundação para a Ciência e Tecnologia, Portugal. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] (RMR); [email protected] (CJ)