TCF12 is mutated in anaplastic oligodendroglioma.

Karim Labreche,Sabrina Hallout,Richard S Houlston,Daniel Chubb,Olivier Saulnier,Emmanuelle Huillard,Christopher P Wardell,Mathew Frampton,Vincent Gleize,Aurélien De Reyniès,Iva Simeonova,Marc Sanson,Nabila Elarouci,Caroline Dehais,Yasser Riazalhosseini,Aurélie Kamoun,Tomi Pastinen,Sara E Dobbins,Karima Mokhtari,Éric Letouzé ,G.m Lathrop ,Ahmed Idbaïh ,François Ducray ,Dominique Figarella‐Branger ,Jean‐Yves Delattre ,Diana Zélénika

doi:10.1038/ncomms8207

Abstract

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, which encodes an oligodendrocyte-related transcription factor. Eighty percent of TCF12 mutations identified were in either the bHLH domain, which is important for TCF12 function as a transcription factor, or were frameshift mutations leading to TCF12 truncated for this domain. We show that these mutations compromise TCF12 transcriptional activity and are associated with a more aggressive tumour type. Our analysis provides further insights into the unique and shared pathways driving AO.

Highlights

Anaplastic oligodendroglioma (AO) are rare primary brain tumours that are generally incurable, with heterogeneous prognosis and few treatment targets identified
As previously proposed, the genomic abnormalities in IDHmut-1p/19p co-deleted tumours are consistent with one common mechanism of tumour initiation being through 1p/19q loss, mutation of IDH1 or IDH2 and TERT activation through promoter mutation[2], which in turn predisposes to deactivation of CIC, FUBP1, NOTCH and activating mutations/amplifications in the PI3K pathway
We identified and replicated mutations in TCF12, a basic helix– loop–helix (bHLH) transcription factor that mediates transcription by forming homo- or heterodimers with other bHLH transcription factors

Summary

Introduction

Anaplastic oligodendroglioma (AO) are rare primary brain tumours that are generally incurable, with heterogeneous prognosis and few treatment targets identified. Eighty percent of TCF12 mutations identified were in either the bHLH domain, which is important for TCF12 function as a transcription factor, or were frameshift mutations leading to TCF12 truncated for this domain. We show that these mutations compromise TCF12 transcriptional activity and are associated with a more aggressive tumour type. In addition to previously reported recurrently mutated genes, we report the identification of somatic mutations in TCF12 in AO. These mutations compromise TCF12 transcriptional activity and confer a more aggressive AO phenotype

Methods

Results

Conclusion