title: 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.affiliation: Department of Pathology and Laboratory Medicine, BC Cancer Agency, BC, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Yip
authors.forename: Yaron S
authors.initials: YS
authors.lastname: Butterfield
authors.forename: Olena
authors.initials: O
authors.lastname: Morozova
authors.forename: Suganthi
authors.initials: S
authors.lastname: Chittaranjan
authors.forename: Michael D
authors.initials: MD
authors.lastname: Blough
authors.forename: Jianghong
authors.initials: J
authors.lastname: An
authors.forename: Inanc
authors.initials: I
authors.lastname: Birol
authors.forename: Charles
authors.initials: C
authors.lastname: Chesnelong
authors.forename: Readman
authors.initials: R
authors.lastname: Chiu
authors.forename: Eric
authors.initials: E
authors.lastname: Chuah
authors.forename: Richard
authors.initials: R
authors.lastname: Corbett
authors.forename: Rod
authors.initials: R
authors.lastname: Docking
authors.forename: Marlo
authors.initials: M
authors.lastname: Firme
authors.forename: Martin
authors.initials: M
authors.lastname: Hirst
authors.forename: Shaun
authors.initials: S
authors.lastname: Jackman
authors.forename: Aly
authors.initials: A
authors.lastname: Karsan
authors.forename: Haiyan
authors.initials: H
authors.lastname: Li
authors.forename: David N
authors.initials: DN
authors.lastname: Louis
authors.forename: Alexandra
authors.initials: A
authors.lastname: Maslova
authors.forename: Richard
authors.initials: R
authors.lastname: Moore
authors.forename: Annie
authors.initials: A
authors.lastname: Moradian
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mungall
authors.forename: Marco
authors.initials: M
authors.lastname: Perizzolo
authors.forename: Jenny
authors.initials: J
authors.lastname: Qian
authors.forename: Gloria
authors.initials: G
authors.lastname: Roldan
authors.forename: Eric E
authors.initials: EE
authors.lastname: Smith
authors.forename: Jessica
authors.initials: J
authors.lastname: Tamura-Wells
authors.forename: Nina
authors.initials: N
authors.lastname: Thiessen
authors.forename: Richard
authors.initials: R
authors.lastname: Varhol
authors.forename: Samuel
authors.initials: S
authors.lastname: Weiss
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Sean
authors.initials: S
authors.lastname: Young
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Mungall
authors.forename: Steven J M
authors.initials: SJ
authors.lastname: Jones
authors.forename: Gregg B
authors.initials: GB
authors.lastname: Morin
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Chan
authors.forename: J Gregory
authors.initials: JG
authors.lastname: Cairncross
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D018572:Disease-Free Survival; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D009154:Mutation; D060787:Neoplasm Grading; D009837:Oligodendroglioma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C498610:CIC protein, human; D012097:Repressor Proteins; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
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