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TCF12 is mutated in anaplastic oligodendroglioma.

Labreche K, Simeonova I, Kamoun A, Gleize V, Chubb D, Letouzé E, Riazalhosseini Y, Dobbins SE, Elarouci N, Ducray F, de Reyniès A, Zelenika D, Wardell CP, Frampton M, Saulnier O, Pastinen T, Hallout S, Figarella-Branger D, Dehais C, Idbaih A, Mokhtari K, Delattre JY, Huillard E, Mark Lathrop G, Sanson M, Houlston RS, POLA Netwo - Nat Commun (2015)

Bottom Line: 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.Our analysis provides further insights into the unique and shared pathways driving AO.

View Article: PubMed Central - PubMed

Affiliation: 1] Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK [2] Inserm, U 1127, ICM, F-75013 Paris, France [3] CNRS, UMR 7225, ICM, F-75013 Paris, France [4] Institut du Cerveau et de la Moelle épinière ICM, Paris 75013, France [5] Sorbonne Universités, UPMC Université Paris 06, UMR S 1127, F-75013 Paris, France.

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.

No MeSH data available.


Related in: MedlinePlus

TCF12 is highly expressed in a subset of anaplastic oligodendroglioma.Representative TCF12 immunostainings are shown: (a) wild-type TCF12 tumours show nuclear staining in a heterogeneous cell population. (b–e) Mutant TCF12 tumours show strong nuclear and cytoplasmic staining. (f) Mutant M260fs (resulting in a truncated protein) is associated with 15q21.3 LOH and shows no staining. Scale bar, 50 μm.
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f4: TCF12 is highly expressed in a subset of anaplastic oligodendroglioma.Representative TCF12 immunostainings are shown: (a) wild-type TCF12 tumours show nuclear staining in a heterogeneous cell population. (b–e) Mutant TCF12 tumours show strong nuclear and cytoplasmic staining. (f) Mutant M260fs (resulting in a truncated protein) is associated with 15q21.3 LOH and shows no staining. Scale bar, 50 μm.

Mentions: We evaluated TCF12 expression and subcellular localization for all of our 11 TCF12-mutated tumours (10 AO and 1 oligodendroglioma grade II) and 11 TCF12 wild-type tumours by immunohistochemistry. All TCF12 wild-type tumours showed nuclear expression in a heterogeneous cell population (Fig. 4; Supplementary Fig. 5), whereas several TCF12-mutated tumours showed nuclear and cytoplasmic staining (Fig. 4; Supplementary Fig. 5). Interestingly, mutations abolishing transcriptional activity were associated with increased staining, suggesting inactive mutant protein accumulation.


TCF12 is mutated in anaplastic oligodendroglioma.

Labreche K, Simeonova I, Kamoun A, Gleize V, Chubb D, Letouzé E, Riazalhosseini Y, Dobbins SE, Elarouci N, Ducray F, de Reyniès A, Zelenika D, Wardell CP, Frampton M, Saulnier O, Pastinen T, Hallout S, Figarella-Branger D, Dehais C, Idbaih A, Mokhtari K, Delattre JY, Huillard E, Mark Lathrop G, Sanson M, Houlston RS, POLA Netwo - Nat Commun (2015)

TCF12 is highly expressed in a subset of anaplastic oligodendroglioma.Representative TCF12 immunostainings are shown: (a) wild-type TCF12 tumours show nuclear staining in a heterogeneous cell population. (b–e) Mutant TCF12 tumours show strong nuclear and cytoplasmic staining. (f) Mutant M260fs (resulting in a truncated protein) is associated with 15q21.3 LOH and shows no staining. Scale bar, 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490400&req=5

f4: TCF12 is highly expressed in a subset of anaplastic oligodendroglioma.Representative TCF12 immunostainings are shown: (a) wild-type TCF12 tumours show nuclear staining in a heterogeneous cell population. (b–e) Mutant TCF12 tumours show strong nuclear and cytoplasmic staining. (f) Mutant M260fs (resulting in a truncated protein) is associated with 15q21.3 LOH and shows no staining. Scale bar, 50 μm.
Mentions: We evaluated TCF12 expression and subcellular localization for all of our 11 TCF12-mutated tumours (10 AO and 1 oligodendroglioma grade II) and 11 TCF12 wild-type tumours by immunohistochemistry. All TCF12 wild-type tumours showed nuclear expression in a heterogeneous cell population (Fig. 4; Supplementary Fig. 5), whereas several TCF12-mutated tumours showed nuclear and cytoplasmic staining (Fig. 4; Supplementary Fig. 5). Interestingly, mutations abolishing transcriptional activity were associated with increased staining, suggesting inactive mutant protein accumulation.

Bottom Line: 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.Our analysis provides further insights into the unique and shared pathways driving AO.

View Article: PubMed Central - PubMed

Affiliation: 1] Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK [2] Inserm, U 1127, ICM, F-75013 Paris, France [3] CNRS, UMR 7225, ICM, F-75013 Paris, France [4] Institut du Cerveau et de la Moelle épinière ICM, Paris 75013, France [5] Sorbonne Universités, UPMC Université Paris 06, UMR S 1127, F-75013 Paris, France.

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.

No MeSH data available.


Related in: MedlinePlus