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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 mutations altering the bHLH domain result in impaired transactivation.(a) Schematic view of the wild-type and mutant TCF12 proteins for which the transactivation capacity has been assessed. Upper panel: wild-type human TCF12, functional domains in grey—activation domain 1 (AD1), activation domain 2 (AD2), repressor domain (Rep) and bHLH domain (bHLH). Lower panel: resulting truncated proteins. Black boxes indicate non-related amino-acid sequences resulting from frameshift mutations (fs), and truncated proteins size is in italic. (b) Schematic structure of the bHLH domain of TCF12 (blue) bound to DNA (grey). WT R602 (yellow) and mutant M602 (purple) residues are indicated. (c) E-box-luciferase reporter plasmid (Eb) was transfected alone or in combination with TCF12 wild-type or mutant expression plasmids. Both frameshift mutants that lack the bHLH DNA binding domain completely abolish TCF12 transcriptional activity. All samples were run in triplicate in four independent experiments. Data were normalized to control renilla luciferase. Values are mean±s.d. ***P=0.0002, **P=0.0018 (Student's t-test).
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f3: TCF12 mutations altering the bHLH domain result in impaired transactivation.(a) Schematic view of the wild-type and mutant TCF12 proteins for which the transactivation capacity has been assessed. Upper panel: wild-type human TCF12, functional domains in grey—activation domain 1 (AD1), activation domain 2 (AD2), repressor domain (Rep) and bHLH domain (bHLH). Lower panel: resulting truncated proteins. Black boxes indicate non-related amino-acid sequences resulting from frameshift mutations (fs), and truncated proteins size is in italic. (b) Schematic structure of the bHLH domain of TCF12 (blue) bound to DNA (grey). WT R602 (yellow) and mutant M602 (purple) residues are indicated. (c) E-box-luciferase reporter plasmid (Eb) was transfected alone or in combination with TCF12 wild-type or mutant expression plasmids. Both frameshift mutants that lack the bHLH DNA binding domain completely abolish TCF12 transcriptional activity. All samples were run in triplicate in four independent experiments. Data were normalized to control renilla luciferase. Values are mean±s.d. ***P=0.0002, **P=0.0018 (Student's t-test).

Mentions: To explore the functional consequences of TCF12 mutation, we tested the transcriptional activity of several mutants (Fig. 3). We tested the frameshift mutations M260fs*5 and E548fs*13, which in the germline cause coronal craniosynostosis10 and S682fs*14, since introduction of a C-terminal premature stop codon may result in escape from non-sense-mediated decay. We also tested the missense mutation R602M, which is predicted to destabilize the bHLH domain required for DNA binding and dimerization (Fig. 3) and whose adjacent residue (R603) has been found recurrently mutated in colon cancer16. Finally, we tested the missense mutation R326S, since mutations of adjacent G327 have been reported in lung adenocarcinoma17. The frameshift mutants M260fs*5 and E548fs*13 completely abolished TCF12 transactivation, consistent with the lack of bHLH DNA-binding domain (Fig. 3). R602M retained only 34% of WT transcriptional activity (P=0.0018, Student's t-test; Fig. 3). We did not observe significant modulation of transactivation for the R326S and S682fs*14 mutants, although the latter consistently showed decreased activity (Fig. 3).


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 mutations altering the bHLH domain result in impaired transactivation.(a) Schematic view of the wild-type and mutant TCF12 proteins for which the transactivation capacity has been assessed. Upper panel: wild-type human TCF12, functional domains in grey—activation domain 1 (AD1), activation domain 2 (AD2), repressor domain (Rep) and bHLH domain (bHLH). Lower panel: resulting truncated proteins. Black boxes indicate non-related amino-acid sequences resulting from frameshift mutations (fs), and truncated proteins size is in italic. (b) Schematic structure of the bHLH domain of TCF12 (blue) bound to DNA (grey). WT R602 (yellow) and mutant M602 (purple) residues are indicated. (c) E-box-luciferase reporter plasmid (Eb) was transfected alone or in combination with TCF12 wild-type or mutant expression plasmids. Both frameshift mutants that lack the bHLH DNA binding domain completely abolish TCF12 transcriptional activity. All samples were run in triplicate in four independent experiments. Data were normalized to control renilla luciferase. Values are mean±s.d. ***P=0.0002, **P=0.0018 (Student's t-test).
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Related In: Results  -  Collection

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

f3: TCF12 mutations altering the bHLH domain result in impaired transactivation.(a) Schematic view of the wild-type and mutant TCF12 proteins for which the transactivation capacity has been assessed. Upper panel: wild-type human TCF12, functional domains in grey—activation domain 1 (AD1), activation domain 2 (AD2), repressor domain (Rep) and bHLH domain (bHLH). Lower panel: resulting truncated proteins. Black boxes indicate non-related amino-acid sequences resulting from frameshift mutations (fs), and truncated proteins size is in italic. (b) Schematic structure of the bHLH domain of TCF12 (blue) bound to DNA (grey). WT R602 (yellow) and mutant M602 (purple) residues are indicated. (c) E-box-luciferase reporter plasmid (Eb) was transfected alone or in combination with TCF12 wild-type or mutant expression plasmids. Both frameshift mutants that lack the bHLH DNA binding domain completely abolish TCF12 transcriptional activity. All samples were run in triplicate in four independent experiments. Data were normalized to control renilla luciferase. Values are mean±s.d. ***P=0.0002, **P=0.0018 (Student's t-test).
Mentions: To explore the functional consequences of TCF12 mutation, we tested the transcriptional activity of several mutants (Fig. 3). We tested the frameshift mutations M260fs*5 and E548fs*13, which in the germline cause coronal craniosynostosis10 and S682fs*14, since introduction of a C-terminal premature stop codon may result in escape from non-sense-mediated decay. We also tested the missense mutation R602M, which is predicted to destabilize the bHLH domain required for DNA binding and dimerization (Fig. 3) and whose adjacent residue (R603) has been found recurrently mutated in colon cancer16. Finally, we tested the missense mutation R326S, since mutations of adjacent G327 have been reported in lung adenocarcinoma17. The frameshift mutants M260fs*5 and E548fs*13 completely abolished TCF12 transactivation, consistent with the lack of bHLH DNA-binding domain (Fig. 3). R602M retained only 34% of WT transcriptional activity (P=0.0018, Student's t-test; Fig. 3). We did not observe significant modulation of transactivation for the R326S and S682fs*14 mutants, although the latter consistently showed decreased activity (Fig. 3).

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