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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

Significantly mutated genes in anaplastic oligodendroglioma by molecular subtype.Significantly mutated genes (Q-value<0.1) identified by exome sequencing are listed by Q-value. The percentage of AO samples with mutation detected by automated calling is detailed on the left. Samples are displayed as columns, with the mutation rate plotted at the top. Samples are arranged to emphasize mutual exclusivity. Mutation types are indicated in different colours (see legend). White colour indicates no information available. Also shown is the relative proportion of base-pair substitutions within mutation categories for each tumour.
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f1: Significantly mutated genes in anaplastic oligodendroglioma by molecular subtype.Significantly mutated genes (Q-value<0.1) identified by exome sequencing are listed by Q-value. The percentage of AO samples with mutation detected by automated calling is detailed on the left. Samples are displayed as columns, with the mutation rate plotted at the top. Samples are arranged to emphasize mutual exclusivity. Mutation types are indicated in different colours (see legend). White colour indicates no information available. Also shown is the relative proportion of base-pair substitutions within mutation categories for each tumour.

Mentions: We performed whole-exome sequencing of 51 AO tumours (Supplementary Data 1) and matched germline DNA, targeting 318,362 exons from 18,901 genes. The mean sequencing coverage across targeted bases was 57 × , with 80% of target bases above 20 × coverage (Supplementary Fig. 1). We identified a total of 4,733 mutations (with a mean of 37 non-silent mutations per sample) equating to a mean somatic mutation rate of 1.62 mutations per megabase (Mb) (Fig. 1). Although the tumours of two patients (3,063 and 3,149) had high rates of mutation (9.1 and 12.4, respectively), this was not reflective of tumour site (both frontal lesions as were 68% of the whole series) or treatment. Excluding these two cases the mean rate of non-silent mutations per tumour was 33±14, which is similar to the number found in most common adult brain tumours. The mutation spectrum in AO tumours was characterized by a predominance of C>T transitions, as observed in most solid cancers (Fig. 1)89. While few of the tumours were IDHwt, these did not harbour a significantly higher number of mutations compared with IDHmut-1p/19q co-deleted and IDHmut-non-1p/19q co-deleted tumours (Fig. 1). Intriguingly, one tumour (2,688) was co-mutated for IDH1 (R132H) and IDH2 (P162S), but exhibited no distinguishing phenotype in terms of clinicopathology or mutation rate.


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)

Significantly mutated genes in anaplastic oligodendroglioma by molecular subtype.Significantly mutated genes (Q-value<0.1) identified by exome sequencing are listed by Q-value. The percentage of AO samples with mutation detected by automated calling is detailed on the left. Samples are displayed as columns, with the mutation rate plotted at the top. Samples are arranged to emphasize mutual exclusivity. Mutation types are indicated in different colours (see legend). White colour indicates no information available. Also shown is the relative proportion of base-pair substitutions within mutation categories for each tumour.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Significantly mutated genes in anaplastic oligodendroglioma by molecular subtype.Significantly mutated genes (Q-value<0.1) identified by exome sequencing are listed by Q-value. The percentage of AO samples with mutation detected by automated calling is detailed on the left. Samples are displayed as columns, with the mutation rate plotted at the top. Samples are arranged to emphasize mutual exclusivity. Mutation types are indicated in different colours (see legend). White colour indicates no information available. Also shown is the relative proportion of base-pair substitutions within mutation categories for each tumour.
Mentions: We performed whole-exome sequencing of 51 AO tumours (Supplementary Data 1) and matched germline DNA, targeting 318,362 exons from 18,901 genes. The mean sequencing coverage across targeted bases was 57 × , with 80% of target bases above 20 × coverage (Supplementary Fig. 1). We identified a total of 4,733 mutations (with a mean of 37 non-silent mutations per sample) equating to a mean somatic mutation rate of 1.62 mutations per megabase (Mb) (Fig. 1). Although the tumours of two patients (3,063 and 3,149) had high rates of mutation (9.1 and 12.4, respectively), this was not reflective of tumour site (both frontal lesions as were 68% of the whole series) or treatment. Excluding these two cases the mean rate of non-silent mutations per tumour was 33±14, which is similar to the number found in most common adult brain tumours. The mutation spectrum in AO tumours was characterized by a predominance of C>T transitions, as observed in most solid cancers (Fig. 1)89. While few of the tumours were IDHwt, these did not harbour a significantly higher number of mutations compared with IDHmut-1p/19q co-deleted and IDHmut-non-1p/19q co-deleted tumours (Fig. 1). Intriguingly, one tumour (2,688) was co-mutated for IDH1 (R132H) and IDH2 (P162S), but exhibited no distinguishing phenotype in terms of clinicopathology or mutation rate.

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