Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers.

Abstract

Oligodendroglioma is characterized by unique clinical, pathological, and genetic features. Recurrent losses of chromosomes 1p and 19q are strongly associated with this brain cancer but knowledge of the identity and function of the genes affected by these alterations is limited. We performed exome sequencing on a discovery set of 16 oligodendrogliomas with 1p/19q co-deletion to identify new molecular features at base-pair resolution. As anticipated, there was a high rate of IDH mutations: all cases had mutations in either IDH1 (14/16) or IDH2 (2/16). In addition, we discovered somatic mutations and insertions/deletions in the CIC gene on chromosome 19q13.2 in 13/16 tumours. These discovery set mutations were validated by deep sequencing of 13 additional tumours, which revealed seven others with CIC mutations, thus bringing the overall mutation rate in oligodendrogliomas in this study to 20/29 (69%). In contrast, deep sequencing of astrocytomas and oligoastrocytomas without 1p/19q loss revealed that CIC alterations were otherwise rare (1/60; 2%). Of the 21 non-synonymous somatic mutations in 20 CIC-mutant oligodendrogliomas, nine were in exon 5 within an annotated DNA-interacting domain and three were in exon 20 within an annotated protein-interacting domain. The remaining nine were found in other exons and frequently included truncations. CIC mutations were highly associated with oligodendroglioma histology, 1p/19q co-deletion, and IDH1/2 mutation (p < 0.001). Although we observed no differences in the clinical outcomes of CIC mutant versus wild-type tumours, in a background of 1p/19q co-deletion, hemizygous CIC mutations are likely important. We hypothesize that the mutant CIC on the single retained 19q allele is linked to the pathogenesis of oligodendrogliomas with IDH mutation. Our detailed study of genetic aberrations in oligodendroglioma suggests a functional interaction between CIC mutation, IDH1/2 mutation, and 1p/19q co-deletion.

• Authors: Stephen Yip, Yaron S Butterfield, Olena Morozova, Suganthi Chittaranjan, Michael D Blough, Jianghong An, Inanc Birol, Charles Chesnelong, Readman Chiu, Eric Chuah, Richard Corbett, Rod Docking, Marlo Firme, Martin Hirst, Shaun Jackman, Aly Karsan, Haiyan Li, David N Louis, Alexandra Maslova, Richard Moore, Annie Moradian, Karen L Mungall, Marco Perizzolo, Jenny Qian, Gloria Roldan, Eric E Smith, Jessica Tamura-Wells, Nina Thiessen, Richard Varhol, Samuel Weiss, Wei Wu, Sean Young, Yongjun Zhao, Andrew J Mungall, Steven J M Jones, Gregg B Morin, Jennifer A Chan, J Gregory Cairncross, Marco A Marra
• Journal: The Journal of pathology (J Pathol) Vol. 226 Issue 1 Pg. 7-16 (Jan 2012) ISSN: 1096-9896 [Electronic] England
• PMID: 22072542 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemical References

• Biomarkers, Tumor
• CIC protein, human
• Repressor Proteins
• IDH2 protein, human
• Isocitrate Dehydrogenase
• IDH1 protein, human

Topics

• Biomarkers, Tumor (analysis, genetics)
• Brain Neoplasms (genetics, mortality, pathology)
• Chromosomes, Human, Pair 1 (genetics)
• Chromosomes, Human, Pair 19 (genetics)
• Disease-Free Survival
• Humans
• Isocitrate Dehydrogenase (genetics)
• Kaplan-Meier Estimate
• Mutation
• Neoplasm Grading
• Oligodendroglioma (genetics, mortality, pathology)
• Repressor Proteins (genetics)