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