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TERT promoter mutations and telomere length in adult malignant gliomas and recurrences.

Heidenreich B, Rachakonda PS, Hosen I, Volz F, Hemminki K, Weyerbrock A, Kumar R - Oncotarget (2015)

Bottom Line: Tumors with TERT promoter mutations compared to those without showed increased TERT transcription; we also showed difference in the transcription levels due to the two main mutations.TERT promoter mutations in low grade gliomas associated with reduced progression free survival (HR 10.2; 95% CI 1.9 - 55.9).While our data affirm the role of TERT promoter mutations in glial tumors, effects on transcription and telomere length emphasise the importance of telomere biology in disease genesis and outcome.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg 69120, Germany.

ABSTRACT
In this report on 303 gliomas we show the highest frequency of TERT promoter mutations in gliobastomas (80%) followed by oligodendrogliomas (70%) and astrocytomas (39%). We observed positive association between TERT promoter and IDH mutations in oligodendroglial tumors (OR = 26.3; 95% CI 2.5-250.2) and inverse association in primary glioblastomas (OR = 0.13; 95% CI 0.03-0.58). Tumors with TERT promoter mutations compared to those without showed increased TERT transcription; we also showed difference in the transcription levels due to the two main mutations. Tumors with TERT promoter mutations had shorter telomeres than those without. The patients with only TERT promoter mutations showed worst survival (median survival 14.6 months) and patients with both IDH and TERT promoter mutations showed best survival (246.5 months). In patients with astrocytoma, the TERT promoter mutations only associated with poor survival (P < 0.0001); IDH mutations and 1p/19q deletions associated with increased survival (P = 0.0004). TERT promoter mutations in low grade gliomas associated with reduced progression free survival (HR 10.2; 95% CI 1.9 - 55.9). While our data affirm the role of TERT promoter mutations in glial tumors, effects on transcription and telomere length emphasise the importance of telomere biology in disease genesis and outcome.

No MeSH data available.


Related in: MedlinePlus

Relative TERT expression in glioma samples according to mutation status of the TERT promoterComparison of TERT mRNA expression in gliomas without and with TERT promoter mutations –124C > T or –146C > T. Expression of TERT gene was normalized to GUSB expression, used as an internal standard, and quantification was performed by ΔΔCT method with log2 transformation. Experiments were carried out in triplicates and box plots represent mean ± standard error of means; P (wildtype/–146C > T) < 0.0001; P (Wildtype/–124C > T) < 0.0001; P (–146C > T/–124C > T) < 0.0001. P-values were determined by t-test.
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Figure 2: Relative TERT expression in glioma samples according to mutation status of the TERT promoterComparison of TERT mRNA expression in gliomas without and with TERT promoter mutations –124C > T or –146C > T. Expression of TERT gene was normalized to GUSB expression, used as an internal standard, and quantification was performed by ΔΔCT method with log2 transformation. Experiments were carried out in triplicates and box plots represent mean ± standard error of means; P (wildtype/–146C > T) < 0.0001; P (Wildtype/–124C > T) < 0.0001; P (–146C > T/–124C > T) < 0.0001. P-values were determined by t-test.

Mentions: RNA was available from 111 gliomas, of which 88 carried TERT promoter mutations (–124C > T n = 67; –146C > T n = 21) and 23 were without the mutations. Analysis of quantitative real-time PCR data showed statistically significant higher levels of mRNA in gliomas with TERT promoter mutations than in wildtype tumors (P < 0.0001, t-test; Figure 2). Tumors harboring the –124C > T mutation had a 14-fold increase in mRNA expression compared to wildtype lesions, whereas –146C > T tumors displayed a 7-fold increase. The difference in expression between tumors with –124C > T and –146C > T mutation was statistically significant (P < 0.0001, t-test; Figure 2).


TERT promoter mutations and telomere length in adult malignant gliomas and recurrences.

Heidenreich B, Rachakonda PS, Hosen I, Volz F, Hemminki K, Weyerbrock A, Kumar R - Oncotarget (2015)

Relative TERT expression in glioma samples according to mutation status of the TERT promoterComparison of TERT mRNA expression in gliomas without and with TERT promoter mutations –124C > T or –146C > T. Expression of TERT gene was normalized to GUSB expression, used as an internal standard, and quantification was performed by ΔΔCT method with log2 transformation. Experiments were carried out in triplicates and box plots represent mean ± standard error of means; P (wildtype/–146C > T) < 0.0001; P (Wildtype/–124C > T) < 0.0001; P (–146C > T/–124C > T) < 0.0001. P-values were determined by t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496380&req=5

Figure 2: Relative TERT expression in glioma samples according to mutation status of the TERT promoterComparison of TERT mRNA expression in gliomas without and with TERT promoter mutations –124C > T or –146C > T. Expression of TERT gene was normalized to GUSB expression, used as an internal standard, and quantification was performed by ΔΔCT method with log2 transformation. Experiments were carried out in triplicates and box plots represent mean ± standard error of means; P (wildtype/–146C > T) < 0.0001; P (Wildtype/–124C > T) < 0.0001; P (–146C > T/–124C > T) < 0.0001. P-values were determined by t-test.
Mentions: RNA was available from 111 gliomas, of which 88 carried TERT promoter mutations (–124C > T n = 67; –146C > T n = 21) and 23 were without the mutations. Analysis of quantitative real-time PCR data showed statistically significant higher levels of mRNA in gliomas with TERT promoter mutations than in wildtype tumors (P < 0.0001, t-test; Figure 2). Tumors harboring the –124C > T mutation had a 14-fold increase in mRNA expression compared to wildtype lesions, whereas –146C > T tumors displayed a 7-fold increase. The difference in expression between tumors with –124C > T and –146C > T mutation was statistically significant (P < 0.0001, t-test; Figure 2).

Bottom Line: Tumors with TERT promoter mutations compared to those without showed increased TERT transcription; we also showed difference in the transcription levels due to the two main mutations.TERT promoter mutations in low grade gliomas associated with reduced progression free survival (HR 10.2; 95% CI 1.9 - 55.9).While our data affirm the role of TERT promoter mutations in glial tumors, effects on transcription and telomere length emphasise the importance of telomere biology in disease genesis and outcome.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg 69120, Germany.

ABSTRACT
In this report on 303 gliomas we show the highest frequency of TERT promoter mutations in gliobastomas (80%) followed by oligodendrogliomas (70%) and astrocytomas (39%). We observed positive association between TERT promoter and IDH mutations in oligodendroglial tumors (OR = 26.3; 95% CI 2.5-250.2) and inverse association in primary glioblastomas (OR = 0.13; 95% CI 0.03-0.58). Tumors with TERT promoter mutations compared to those without showed increased TERT transcription; we also showed difference in the transcription levels due to the two main mutations. Tumors with TERT promoter mutations had shorter telomeres than those without. The patients with only TERT promoter mutations showed worst survival (median survival 14.6 months) and patients with both IDH and TERT promoter mutations showed best survival (246.5 months). In patients with astrocytoma, the TERT promoter mutations only associated with poor survival (P < 0.0001); IDH mutations and 1p/19q deletions associated with increased survival (P = 0.0004). TERT promoter mutations in low grade gliomas associated with reduced progression free survival (HR 10.2; 95% CI 1.9 - 55.9). While our data affirm the role of TERT promoter mutations in glial tumors, effects on transcription and telomere length emphasise the importance of telomere biology in disease genesis and outcome.

No MeSH data available.


Related in: MedlinePlus