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High level of telomerase RNA gene expression is associated with chromatin modification, the ALT phenotype and poor prognosis in liposarcoma.

Cairney CJ, Hoare SF, Daidone MG, Zaffaroni N, Keith WN - Br. J. Cancer (2008)

Bottom Line: The ALT pathway is more commonly activated in tumours of mesenchymal origin, although the mechanisms involved in the decision of a cell to activate either telomerase or ALT are unknown at present and no molecular markers exist to define the ALT phenotype.We have previously shown an association between chromatin remodelling, telomerase gene expression and ALT in cell line models.Investigation of a small panel of chromatin modifications revealed significantly increased binding of acetyl H3 in association with hTR expression.

View Article: PubMed Central - PubMed

Affiliation: Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK Beatson Laboratories, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.

ABSTRACT
Telomere length is maintained by two known mechanisms, activation of telomerase or alternative lengthening of telomeres (ALT). The ALT pathway is more commonly activated in tumours of mesenchymal origin, although the mechanisms involved in the decision of a cell to activate either telomerase or ALT are unknown at present and no molecular markers exist to define the ALT phenotype. We have previously shown an association between chromatin remodelling, telomerase gene expression and ALT in cell line models. Here, we evaluate these findings and investigate their prognostic significance in a panel of liposarcoma tissue samples to understand the biology underlying the ALT phenotype. Liposarcoma samples were split into three groups: telomerase positive (Tel+); ALT positive; ALT-/Tel-. Differences in telomerase gene expression were evident between the groups with increased expression of hTR in ALT and Tel+ compared to ALT-/Tel- samples and increased hTERT in Tel+ samples only. Investigation of a small panel of chromatin modifications revealed significantly increased binding of acetyl H3 in association with hTR expression. We confirm that the presence of the ALT phenotype is associated with poor prognosis and in addition, for the first time, we show a direct association between hTR expression and poor prognosis in liposarcoma patients.

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Related in: MedlinePlus

Telomerase gene expression in liposarcoma samples. (A) hTR expression taken as a percentage of the riboprotein S15; (B) total hTERT expression in ng per μl. The grey box defines 25 and 75% quartiles, while error bars represent the first and 99th percentiles of the distribution. Dots represent outliers and the black line defines the median of the distribution. P-values were calculated using the Kruskal–Wallis test, which tests the likelihood of all medians being the same. (C) Four major hTERT splice variant PCR products were quantified using the Agilent Bioanalyser.
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fig1: Telomerase gene expression in liposarcoma samples. (A) hTR expression taken as a percentage of the riboprotein S15; (B) total hTERT expression in ng per μl. The grey box defines 25 and 75% quartiles, while error bars represent the first and 99th percentiles of the distribution. Dots represent outliers and the black line defines the median of the distribution. P-values were calculated using the Kruskal–Wallis test, which tests the likelihood of all medians being the same. (C) Four major hTERT splice variant PCR products were quantified using the Agilent Bioanalyser.

Mentions: hTR expression, normalised to expression of the riboprotein S15, was determined by Q-PCR and expressed as a percentage of S15 (Figure 1A). All of the liposarcoma samples evaluated in this study expressed hTR to varying degrees; however, significant differences in expression were found within the three groups (P=0.05). Samples that were negative for both telomerase and ALT had mostly low-level expression with a median level of 48% of S15 expression (range 20–333%), while those that were Tel+ had an even distribution of expression with a median level of 242% (range 31–562% with one outlier at 1783%). Those samples expressing the ALT phenotype, on the other hand, appeared to have a higher distribution of expression, although the median value of 199% did not reflect this (range 71–653% with one outlier at 3575%).


High level of telomerase RNA gene expression is associated with chromatin modification, the ALT phenotype and poor prognosis in liposarcoma.

Cairney CJ, Hoare SF, Daidone MG, Zaffaroni N, Keith WN - Br. J. Cancer (2008)

Telomerase gene expression in liposarcoma samples. (A) hTR expression taken as a percentage of the riboprotein S15; (B) total hTERT expression in ng per μl. The grey box defines 25 and 75% quartiles, while error bars represent the first and 99th percentiles of the distribution. Dots represent outliers and the black line defines the median of the distribution. P-values were calculated using the Kruskal–Wallis test, which tests the likelihood of all medians being the same. (C) Four major hTERT splice variant PCR products were quantified using the Agilent Bioanalyser.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2361713&req=5

fig1: Telomerase gene expression in liposarcoma samples. (A) hTR expression taken as a percentage of the riboprotein S15; (B) total hTERT expression in ng per μl. The grey box defines 25 and 75% quartiles, while error bars represent the first and 99th percentiles of the distribution. Dots represent outliers and the black line defines the median of the distribution. P-values were calculated using the Kruskal–Wallis test, which tests the likelihood of all medians being the same. (C) Four major hTERT splice variant PCR products were quantified using the Agilent Bioanalyser.
Mentions: hTR expression, normalised to expression of the riboprotein S15, was determined by Q-PCR and expressed as a percentage of S15 (Figure 1A). All of the liposarcoma samples evaluated in this study expressed hTR to varying degrees; however, significant differences in expression were found within the three groups (P=0.05). Samples that were negative for both telomerase and ALT had mostly low-level expression with a median level of 48% of S15 expression (range 20–333%), while those that were Tel+ had an even distribution of expression with a median level of 242% (range 31–562% with one outlier at 1783%). Those samples expressing the ALT phenotype, on the other hand, appeared to have a higher distribution of expression, although the median value of 199% did not reflect this (range 71–653% with one outlier at 3575%).

Bottom Line: The ALT pathway is more commonly activated in tumours of mesenchymal origin, although the mechanisms involved in the decision of a cell to activate either telomerase or ALT are unknown at present and no molecular markers exist to define the ALT phenotype.We have previously shown an association between chromatin remodelling, telomerase gene expression and ALT in cell line models.Investigation of a small panel of chromatin modifications revealed significantly increased binding of acetyl H3 in association with hTR expression.

View Article: PubMed Central - PubMed

Affiliation: Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK Beatson Laboratories, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.

ABSTRACT
Telomere length is maintained by two known mechanisms, activation of telomerase or alternative lengthening of telomeres (ALT). The ALT pathway is more commonly activated in tumours of mesenchymal origin, although the mechanisms involved in the decision of a cell to activate either telomerase or ALT are unknown at present and no molecular markers exist to define the ALT phenotype. We have previously shown an association between chromatin remodelling, telomerase gene expression and ALT in cell line models. Here, we evaluate these findings and investigate their prognostic significance in a panel of liposarcoma tissue samples to understand the biology underlying the ALT phenotype. Liposarcoma samples were split into three groups: telomerase positive (Tel+); ALT positive; ALT-/Tel-. Differences in telomerase gene expression were evident between the groups with increased expression of hTR in ALT and Tel+ compared to ALT-/Tel- samples and increased hTERT in Tel+ samples only. Investigation of a small panel of chromatin modifications revealed significantly increased binding of acetyl H3 in association with hTR expression. We confirm that the presence of the ALT phenotype is associated with poor prognosis and in addition, for the first time, we show a direct association between hTR expression and poor prognosis in liposarcoma patients.

Show MeSH
Related in: MedlinePlus