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Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age.

ABSTRACT: Pilocytic astrocytoma (PA) is the most common brain tumor in children but is rare in adults, and hence poorly studied in this age group. We investigated 222 PA and report increased aneuploidy in older patients. Aneuploid genomes were identified in 45% of adult compared with 17% of pediatric PA. Gains were non-random, favoring chromosomes 5, 7, 6 and 11 in order of frequency, and preferentially affecting non-cerebellar PA and tumors with BRAF V600E mutations and not with KIAA1549-BRAF fusions or FGFR1 mutations. Aneuploid PA differentially expressed genes involved in CNS development, the unfolded protein response, and regulators of genomic stability and the cell cycle (MDM2, PLK2),whose correlated programs were overexpressed specifically in aneuploid PA compared to other glial tumors. Thus, convergence of pathways affecting the cell cycle and genomic stability may favor aneuploidy in PA, possibly representing an additional molecular driver in older patients with this brain tumor.

SUBMITTER: Fontebasso AM

PROVIDER: S-EPMC4741644 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age.

Fontebasso Adam M AM Shirinian Margret M Khuong-Quang Dong-Anh DA Bechet Denise D Gayden Tenzin T Kool Marcel M De Jay Nicolas N Jacob Karine K Gerges Noha N Hutter Barbara B Şeker-Cin Huriye H Witt Hendrik H Montpetit Alexandre A Brunet Sébastien S Lepage Pierre P Bourret Geneviève G Klekner Almos A Bognár László L Hauser Peter P Garami Miklós M Farmer Jean-Pierre JP Montes Jose-Luis JL Atkinson Jeffrey J Lambert Sally S Kwan Tony T Korshunov Andrey A Tabori Uri U Collins V Peter VP Albrecht Steffen S Faury Damien D Pfister Stefan M SM Paulus Werner W Hasselblatt Martin M Jones David T W DT Jabado Nada N

Oncotarget 20151001 31

Pilocytic astrocytoma (PA) is the most common brain tumor in children but is rare in adults, and hence poorly studied in this age group. We investigated 222 PA and report increased aneuploidy in older patients. Aneuploid genomes were identified in 45% of adult compared with 17% of pediatric PA. Gains were non-random, favoring chromosomes 5, 7, 6 and 11 in order of frequency, and preferentially affecting non-cerebellar PA and tumors with BRAF V600E mutations and not with KIAA1549-BRAF fusions or ...[more]

PMID: 26378811

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Project description:BackgroundPilocytic Astrocytomas (PAs) are common low-grade central nervous system malignancies for which few recurrent and specific genetic alterations have been identified. In an effort to better understand the molecular biology underlying the pathogenesis of these pediatric brain tumors, we performed higher-order transcriptional network analysis of a large gene expression dataset to identify gene regulatory pathways that are specific to this tumor type, relative to other, more aggressive glial or histologically distinct brain tumours.MethodsRNA derived from frozen human PA tumours was subjected to microarray-based gene expression profiling, using Affymetrix U133Plus2 GeneChip microarrays. This data set was compared to similar data sets previously generated from non-malignant human brain tissue and other brain tumour types, after appropriate normalization.ResultsIn this study, we examined gene expression in 66 PA tumors compared to 15 non-malignant cortical brain tissues, and identified 792 genes that demonstrated consistent differential expression between independent sets of PA and non-malignant specimens. From this entire 792 gene set, we used the previously described PAP tool to assemble a core transcriptional regulatory network composed of 6 transcription factor genes (TFs) and 24 target genes, for a total of 55 interactions. A similar analysis of oligodendroglioma and glioblastoma multiforme (GBM) gene expression data sets identified distinct, but overlapping, networks. Most importantly, comparison of each of the brain tumor type-specific networks revealed a network unique to PA that included repressed expression of ONECUT2, a gene frequently methylated in other tumor types, and 13 other uniquely predicted TF-gene interactions.ConclusionsThese results suggest specific transcriptional pathways that may operate to create the unique molecular phenotype of PA and thus opportunities for corresponding targeted therapeutic intervention. Moreover, this study also demonstrates how integration of gene expression data with TF-gene and TF-TF interaction data is a powerful approach to generating testable hypotheses to better understand cell-type specific genetic programs relevant to cancer.

Dataset Information

Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age.

Publications

Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age.

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