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Inference of Low and High-Grade Glioma Gene Regulatory Networks Delineates the Role of Rnd3 in Establishing Multiple Hallmarks of Cancer.

Clarke K, Daubon T, Turan N, Soulet F, Mohd Zahari M, Ryan KR, Durant S, He S, Herbert J, Ankers J, Heath JK, Bjerkvig R, Bicknell R, Hotchin NA, Bikfalvi A, Falciani F - PLoS Genet. (2015)

Bottom Line: Glioblastoma patients have an average survival time of less than 15 months.The first one is involved in maintaining normal glial cell function, while the second is linked to the establishment of multiple hallmarks of cancer.Next, the development and application of a novel data integration methodology reveals novel functions of RND3 in controlling glioma cell migration, invasion, proliferation, angiogenesis and clinical outcome.

View Article: PubMed Central - PubMed

Affiliation: Centre for Computational Biology and Modelling (CCBM), Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom; INSERM U1029, University Bordeaux, Pessac, France.

ABSTRACT
Gliomas are a highly heterogeneous group of brain tumours that are refractory to treatment, highly invasive and pro-angiogenic. Glioblastoma patients have an average survival time of less than 15 months. Understanding the molecular basis of different grades of glioma, from well differentiated, low-grade tumours to high-grade tumours, is a key step in defining new therapeutic targets. Here we use a data-driven approach to learn the structure of gene regulatory networks from observational data and use the resulting models to formulate hypothesis on the molecular determinants of glioma stage. Remarkably, integration of available knowledge with functional genomics datasets representing clinical and pre-clinical studies reveals important properties within the regulatory circuits controlling low and high-grade glioma. Our analyses first show that low and high-grade gliomas are characterised by a switch in activity of two subsets of Rho GTPases. The first one is involved in maintaining normal glial cell function, while the second is linked to the establishment of multiple hallmarks of cancer. Next, the development and application of a novel data integration methodology reveals novel functions of RND3 in controlling glioma cell migration, invasion, proliferation, angiogenesis and clinical outcome.

No MeSH data available.


Related in: MedlinePlus

RND3 expression and copy number variation is a significant risk factor for glioma patients.A. The Kaplan-Meier survival curves for glioma patients with amplification (red, n = 45) or deletion (green, n = 72) of the RND3 locus, determined from SNP frequency data within the REMBRANDT database, log rank p value = 0.0301. B. The Kaplan-Meier survival curves for glioma patients with RND3 overexpression (red, n = 89) or comparable expression (orange, n = 88) versus non-tumour samples, log rank p value = 0.0006. All analysis performed using the online REMBRANDT database tools.
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pgen.1005325.g007: RND3 expression and copy number variation is a significant risk factor for glioma patients.A. The Kaplan-Meier survival curves for glioma patients with amplification (red, n = 45) or deletion (green, n = 72) of the RND3 locus, determined from SNP frequency data within the REMBRANDT database, log rank p value = 0.0301. B. The Kaplan-Meier survival curves for glioma patients with RND3 overexpression (red, n = 89) or comparable expression (orange, n = 88) versus non-tumour samples, log rank p value = 0.0006. All analysis performed using the online REMBRANDT database tools.

Mentions: We first approached this question using data available within the REMBRANT database of functional genomics data [29]. We focused on GBM patients and found that patients with an increased RND3 copy number showed significantly lower probability of survival compared to patients with a normal or reduced RND3 copy number (Fig 7A). Using the same database we then could verify that RND3 gene expression was also predictive of survival and that RND3 CNV and expression were positively correlated (Fig 7B).


Inference of Low and High-Grade Glioma Gene Regulatory Networks Delineates the Role of Rnd3 in Establishing Multiple Hallmarks of Cancer.

Clarke K, Daubon T, Turan N, Soulet F, Mohd Zahari M, Ryan KR, Durant S, He S, Herbert J, Ankers J, Heath JK, Bjerkvig R, Bicknell R, Hotchin NA, Bikfalvi A, Falciani F - PLoS Genet. (2015)

RND3 expression and copy number variation is a significant risk factor for glioma patients.A. The Kaplan-Meier survival curves for glioma patients with amplification (red, n = 45) or deletion (green, n = 72) of the RND3 locus, determined from SNP frequency data within the REMBRANDT database, log rank p value = 0.0301. B. The Kaplan-Meier survival curves for glioma patients with RND3 overexpression (red, n = 89) or comparable expression (orange, n = 88) versus non-tumour samples, log rank p value = 0.0006. All analysis performed using the online REMBRANDT database tools.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4488580&req=5

pgen.1005325.g007: RND3 expression and copy number variation is a significant risk factor for glioma patients.A. The Kaplan-Meier survival curves for glioma patients with amplification (red, n = 45) or deletion (green, n = 72) of the RND3 locus, determined from SNP frequency data within the REMBRANDT database, log rank p value = 0.0301. B. The Kaplan-Meier survival curves for glioma patients with RND3 overexpression (red, n = 89) or comparable expression (orange, n = 88) versus non-tumour samples, log rank p value = 0.0006. All analysis performed using the online REMBRANDT database tools.
Mentions: We first approached this question using data available within the REMBRANT database of functional genomics data [29]. We focused on GBM patients and found that patients with an increased RND3 copy number showed significantly lower probability of survival compared to patients with a normal or reduced RND3 copy number (Fig 7A). Using the same database we then could verify that RND3 gene expression was also predictive of survival and that RND3 CNV and expression were positively correlated (Fig 7B).

Bottom Line: Glioblastoma patients have an average survival time of less than 15 months.The first one is involved in maintaining normal glial cell function, while the second is linked to the establishment of multiple hallmarks of cancer.Next, the development and application of a novel data integration methodology reveals novel functions of RND3 in controlling glioma cell migration, invasion, proliferation, angiogenesis and clinical outcome.

View Article: PubMed Central - PubMed

Affiliation: Centre for Computational Biology and Modelling (CCBM), Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom; INSERM U1029, University Bordeaux, Pessac, France.

ABSTRACT
Gliomas are a highly heterogeneous group of brain tumours that are refractory to treatment, highly invasive and pro-angiogenic. Glioblastoma patients have an average survival time of less than 15 months. Understanding the molecular basis of different grades of glioma, from well differentiated, low-grade tumours to high-grade tumours, is a key step in defining new therapeutic targets. Here we use a data-driven approach to learn the structure of gene regulatory networks from observational data and use the resulting models to formulate hypothesis on the molecular determinants of glioma stage. Remarkably, integration of available knowledge with functional genomics datasets representing clinical and pre-clinical studies reveals important properties within the regulatory circuits controlling low and high-grade glioma. Our analyses first show that low and high-grade gliomas are characterised by a switch in activity of two subsets of Rho GTPases. The first one is involved in maintaining normal glial cell function, while the second is linked to the establishment of multiple hallmarks of cancer. Next, the development and application of a novel data integration methodology reveals novel functions of RND3 in controlling glioma cell migration, invasion, proliferation, angiogenesis and clinical outcome.

No MeSH data available.


Related in: MedlinePlus