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Dataset Information

An expression profiling study of anaplastic oligodendroglioma

ABSTRACT: A Cartes d'Identite des Tumeurs (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net): Anaplastic oligodendrogliomas (AOs) are rare primary brain tumors which are generally incurable with few treatment targets identified. Most oligodendrogliomas have chromosome 1p/19q co-deletion and IDH mutation. We analyzed 51 AOs by whole-exome and/or transcriptome sequencing identifying previously reported frequent somatic mutations in CIC and FUBP1 genes. We also identified recurrent mutations in TCF12 (11% of IDHmut-codel) which encodes basic helix-loop-helix (bHLFH) transcription factor 12; which is an oligodendrocyte-related transcription factor in IDHmut-codel tumors. Strikingly, the somatic mutations (encoding E548R and R602M substitutions) have not been reported previously in cancer but are identical to germline mutations causing craniosynostosis. Incorporating TCGA data on 43 AO tumors also implicates functional mutation of SMARCA4, NOTCH1, NOTCH2, SETD2, RBPJ and ARID1A/1B. These data are compatible with the combined deregulation of metabolism, chromatin organization/remodeling and Notch-pathway genes in AO oncogenesis. Our analysis provides further insights into the unique and shared pathways driving AO and new targets for therapeutic intervention.

INSTRUMENT(S): GeneChip® Scanner 3000 7G (Affymetrix)

ORGANISM(S): Homo sapiens

SUBMITTER: Nabila Elarouci

PROVIDER: E-MTAB-2768 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

TCF12 is mutated in anaplastic oligodendroglioma.

Labreche Karim K Simeonova Iva I Kamoun Aurélie A Gleize Vincent V Chubb Daniel D Letouzé Eric E Riazalhosseini Yasser Y Dobbins Sara E SE Elarouci Nabila N Ducray Francois F de Reyniès Aurélien A Zelenika Diana D Wardell Christopher P CP Frampton Mathew M Saulnier Olivier O Pastinen Tomi T Hallout Sabrina S Figarella-Branger Dominique D Dehais Caroline C Idbaih Ahmed A Mokhtari Karima K Delattre Jean-Yves JY Huillard Emmanuelle E Mark Lathrop G G Sanson Marc M Houlston Richard S RS

Nature communications 20150612

Anaplastic oligodendroglioma (AO) are rare primary brain tumours that are generally incurable, with heterogeneous prognosis and few treatment targets identified. Most oligodendrogliomas have chromosomes 1p/19q co-deletion and an IDH mutation. Here we analysed 51 AO by whole-exome sequencing, identifying previously reported frequent somatic mutations in CIC and FUBP1. We also identified recurrent mutations in TCF12 and in an additional series of 83 AO. Overall, 7.5% of AO are mutated for TCF12, w ...[more]

PMID: 26068201

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Project description:Oligodendrogliomas are defined by IDH-mutations and codeletions of chromosomal arms 1p and 19q. In the past, case reports and small studies described gliomas with sarcomatous features arising from oligodendrogliomas, so called oligosarcomas. Here, we report a series of 23 IDH-mutant oligosarcomas forming a distinct methylation class. The tumors were recurrences from prior oligodendrogliomas or developed de novo. Precursor tumors of 11 oligosarcomas were histologically and molecularly indistinguishable from conventional oligodendrogliomas. Oligosarcoma tumor cells were embedded in a dens network of reticulin fibers, frequently showing p53 accumulation, positivity for SMA, and gain of H3K27 trimethylation (H3K27me3) as compared to primary lesions. In 5 oligosarcomas no 1p/19q codeletion was detectable, although it was present in the primary lesions. Oligosarcomas harbored an increased chromosomal copy number variation load with frequent CDKN2A/B deletions. Proteomic profiling demonstrated oligosarcomas to be highly distinct from conventional grade 3 oligodendrogliomas with consistent evidence for a smooth muscle differentiation. Expression of several tumor suppressors was reduced with NF1 being lost frequently. In contrast, oncogenic YAP1 was aberrantly overexpressed in oligosarcomas. Panel sequencing revealed mutations in NF1 and TP53 along with IDH1/2 and TERT promoter mutations. Survival of patients was significantly poorer for oligosarcomas than for grade 3 oligodendrogliomas and comparable to that of grade 4 IDH-mutant astrocytomas. These results establish oligosarcoma as a distinct type of IDH-mutant glioma differing from conventional oligodendrogliomas on the histologic, epigenetic, proteomic, molecular and clinical level. Diagnosis can be based on the characteristic DNA methylation profile or the combined evidence of sarcomatous histology, IDH-mutation and an oligodendroglioma-typical molecular alteration as TERT promoter mutation and/or 1p/19q codeletion.

Dataset Information

An expression profiling study of anaplastic oligodendroglioma

Publications

TCF12 is mutated in anaplastic oligodendroglioma.

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