Novel CIC point mutations and an exon-spanning, homozygous deletion identified in oligodendroglial tumors by a comprehensive genomic approach including transcriptome sequencing

PLoS One. 2013 Sep 27;8(9):e76623. doi: 10.1371/journal.pone.0076623. eCollection 2013.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Astrocytoma / genetics
  • Chromosome Deletion*
  • Cohort Studies
  • DNA Helicases / genetics
  • DNA-Binding Proteins / genetics
  • Exons / genetics*
  • Female
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic / genetics
  • Genomics*
  • Glioma / genetics*
  • Homozygote
  • Humans
  • Male
  • Middle Aged
  • Oligodendroglioma / genetics
  • Point Mutation*
  • RNA-Binding Proteins
  • Repressor Proteins / genetics*
  • Sequence Analysis, DNA
  • Sequence Analysis, RNA

Substances

  • CIC protein, human
  • DNA-Binding Proteins
  • FUBP1 protein, human
  • RNA-Binding Proteins
  • Repressor Proteins
  • DNA Helicases

Grant support

Part of this work was supported by a grant (MeDDrive programm) of the Medizinische Fakultät Carl Gustav Carus, TU Dresden, awarded to BK, and by the Bundesministerium für Bildung und Forschung within the framework of the Nationales Genomforschungsnetzwerk, grant 01GS08182, to KS and MP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.