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 7 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, 9 were in exon 5 within an annotated DNA interacting domain and 3 were in exon 20 within an annotated protein interacting domain. The remaining 9 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 tumors, 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.

Loss of CIC and FUBP1 expressions are potential markers of shorter time to recurrence in oligodendroglial tumors

“…12 An independent study using a similar approach revealed the presence of CIC mutation but not FUBP1 mutation in oligodendroglioma. 13 Subsequent studies confirmed the presence of CIC and FUBP1 mutations in oligodendroglioma as well as in oligoastrocytoma. 14,15 In contrast, such mutations were rarely found in astrocytoma and glioblastoma.…”

“…14,15 In contrast, such mutations were rarely found in astrocytoma and glioblastoma. [13][14][15] CIC and FUBP1 mutations were strongly associated with 1p/19q codeletion, suggesting that chromosomal loss of 1p and 19q might contribute to inactivation of these genes. The role CIC and FUBP1 has in oligodendroglial tumor development is unclear.…”

“…Considering that a larger proportion of CIC and FUBP1 mutations identified were predicted to be detrimental to CIC and FUBP1 structure or functions, [12][13][14][15] the impact of these mutations on protein expression has not been examined. Moreover, determining protein expression may uncover additional inactivated CIC and FUBP1 not mediated by mutations.…”

Defining neoplastic diseases differently: An emerging paradigm from The Cancer Genome Atlas lower-grade gliomas project

“…6,7 In addition to IDH mutations, these tumors harbored mutations in Capicua transcriptional repressor (CIC), far upstream element binding protein 1 (FUBP1), NOTCH1, and the TERT promoter. Of note, this subset was associated with the most favorable clinical outcomes, with a median survival of 8.0 years, partially due to the well-recognized chemosensitivity of tumors with 1p/19q co-deletion.…”

Analysis of Olig2 and YKL-40 expression: a clinicopathological/immunohistochemical study for the distinction between subventricular zone II and III glioblastomas

“…However, the literature on Olig2 and its asso ciation with glioblastoma prognosis is ambivalent [1,11,12,22]. Recent reports have found associations between glioblastoma and neural stem cells express ing Olig2 [8,12,20,35]. Therefore, a significant amount of the ongoing GB research is focused on better under standing how cells expressing Olig2 contribute to the gliomagenesis and therapeutic targets.…”