Novel CIC Point Mutations and an Exon-Spanning, Homozygous Deletion Identified in Oligodendroglial Tumors by a Comprehensive Genomic Approach Including Transcriptome Sequencing

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Sophie Eisenreich - , Medical Faculty Carl Gustav Carus (Author)
  • Khalil Abou-El-Ardat - , Institute of Clinical Genetics (Author)
  • Karol Szafranski - , Leibniz Institute on Aging - Fritz Lipmann Institute (Author)
  • Jaime A. Campos Valenzuela - , Medical Faculty Carl Gustav Carus (Author)
  • Andreas Rump - , Institute of Clinical Genetics (Author)
  • Janice M. Nigro - , University of Bergen (Author)
  • Rolf Bjerkvig - , University of Bergen (Author)
  • Eva Maria Gerlach - , Medical Faculty Carl Gustav Carus (Author)
  • Karl Hackmann - , Institute of Clinical Genetics (Author)
  • Evelin Schröck - , Institute of Clinical Genetics (Author)
  • Dietmar Krex - , Department of Neurosurgery (Author)
  • Lars Kaderali - , Medical Faculty Carl Gustav Carus (Author)
  • Gabriele Schackert - , TUD Dresden University of Technology (Author)
  • Matthias Platzer - , Leibniz Institute on Aging - Fritz Lipmann Institute (Author)
  • Barbara Klink - , Institute of Clinical Genetics (Author)

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.

Details

Original languageEnglish
Article numbere76623
JournalPLoS ONE
Volume8
Issue number9
Publication statusPublished - 27 Sept 2013
Peer-reviewedYes

External IDs

Scopus 84884691994
researchoutputwizard legacy.publication#55237
researchoutputwizard legacy.publication#54482
PubMed 24086756