title: Microsatellite instability in pediatric high grade glioma is associated with genomic profile and differential target gene inactivation.
abstract: 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.
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Viana-Pereira
authors.forename: Alicia
authors.initials: A
authors.lastname: Lee
authors.forename: Sergey
authors.initials: S
authors.lastname: Popov
authors.forename: Dorine A
authors.initials: DA
authors.lastname: Bax
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Sarraj
authors.forename: Leslie R
authors.initials: LR
authors.lastname: Bridges
authors.forename: João N
authors.initials: JN
authors.lastname: Stávale
authors.forename: Darren
authors.initials: D
authors.lastname: Hargrave
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
authors.forename: Rui M
authors.initials: RM
authors.lastname: Reis
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D002648:Child; D053903:DNA Breaks, Double-Stranded; D053843:DNA Mismatch Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D020868:Gene Silencing; D052138:Genes, Neoplasm / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D005910:Glioma / Q000235:genetics*; D006801:Humans; D007223:Infant; D000076228:MRE11 Homologue Protein; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D000076228:MRE11 Homologue Protein