Novel CIC Point Mutations and an Exon-Spanning, Homozygous Deletion Identified in Oligodendroglial Tumors by a Comprehensive Genomic Approach Including Transcriptome Sequencing
| Autor: | Karl Hackmann, Barbara Klink, Evelin Schröck, Sophie Eisenreich, Rolf Bjerkvig, Janice M. Nigro, Matthias Platzer, Gabriele Schackert, Khalil Abou-El-Ardat, Jaime Alberto Campos Valenzuela, Karol Szafranski, Andreas Rump, Eva-Maria Gerlach, Lars Kaderali, Dietmar Krex |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
Male Mutation rate Science Oligodendroglioma Nonsense mutation Astrocytoma Biology medicine.disease_cause Frameshift mutation Cohort Studies Exon medicine Humans Point Mutation Missense mutation Oligodendroglial Tumor Alleles Genetics Mutation Multidisciplinary Sequence Analysis RNA Gene Expression Profiling Point mutation Homozygote DNA Helicases RNA-Binding Proteins Exons Genomics Glioma Sequence Analysis DNA Middle Aged DNA-Binding Proteins Gene Expression Regulation Neoplastic Repressor Proteins Medicine Female Chromosome Deletion Research Article |
| Zdroj: | PLoS ONE, Vol 8, Iss 9, p e76623 (2013) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Oligodendroglial tumors form a distinct subgroup of gliomas, characterized by a better response to treatment and prolonged overall survival. Most oligodendrogliomas and also some oligoastrocytomas are characterized by a unique and typical unbalanced translocation, der(1,19), resulting in a 1p/19q co-deletion. Candidate tumor suppressor genes targeted by these losses, CIC on 19q13.2 and FUBP1 on 1p31.1, were only recently discovered. We analyzed 17 oligodendrogliomas and oligoastrocytomas by applying a comprehensive approach consisting of RNA expression analysis, DNA sequencing of CIC, FUBP1, IDH1/2, and array CGH. We confirmed three different genetic subtypes in our samples: i) the "oligodendroglial" subtype with 1p/19q co-deletion in twelve out of 17 tumors; ii) the "astrocytic" subtype in three tumors; iii) the "other" subtype in two tumors. All twelve tumors with the 1p/19q co-deletion carried the most common IDH1 R132H mutation. In seven of these tumors, we found protein-disrupting point mutations in the remaining allele of CIC, four of which are novel. One of these tumors also had a deleterious mutation in FUBP1. Only by integrating RNA expression and array CGH data, were we able to discover an exon-spanning homozygous microdeletion within the remaining allele of CIC in an additional tumor with 1p/19q co-deletion. Therefore we propose that the mutation rate might be underestimated when looking at sequence variants alone. In conclusion, the high frequency and the spectrum of CIC mutations in our 1p/19q-codeleted tumor cohort support the hypothesis that CIC acts as a tumor suppressor in these tumors, whereas FUBP1 might play only a minor role. |
| Databáze: | OpenAIRE |
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