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Delineating the cytogenomic and epigenomic landscapes of glioma stem cell lines.

Baronchelli S, Bentivegna A, Redaelli S, Riva G, Butta V, Paoletta L, Isimbaldi G, Miozzo M, Tabano S, Daga A, Marubbi D, Cattaneo M, Biunno I, Dalprà L - PLoS ONE (2013)

Bottom Line: We found several canonical cytogenetic alterations associated with GBM and a common minimal deleted region (MDR) at 1p36.31, including CAMTA1 gene, a putative tumor suppressor gene, specific for the GSC population.Therefore, beyond the differences that can create apparent heterogeneity of alterations among GSC lines, there's a sort of selective force acting on them in order to converge towards the impairment of cell development and differentiation processes.This new overview could have a huge importance in therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery and Translational Medicine, University of Milan-Bicocca, Monza, Italy.

ABSTRACT
Glioblastoma multiforme (GBM), the most common and malignant type of glioma, is characterized by a poor prognosis and the lack of an effective treatment, which are due to a small sub-population of cells with stem-like properties, termed glioma stem cells (GSCs). The term "multiforme" describes the histological features of this tumor, that is, the cellular and morphological heterogeneity. At the molecular level multiple layers of alterations may reflect this heterogeneity providing together the driving force for tumor initiation and development. In order to decipher the common "signature" of the ancestral GSC population, we examined six already characterized GSC lines evaluating their cytogenomic and epigenomic profiles through a multilevel approach (conventional cytogenetic, FISH, aCGH, MeDIP-Chip and functional bioinformatic analysis). We found several canonical cytogenetic alterations associated with GBM and a common minimal deleted region (MDR) at 1p36.31, including CAMTA1 gene, a putative tumor suppressor gene, specific for the GSC population. Therefore, on one hand our data confirm a role of driver mutations for copy number alterations (CNAs) included in the GBM genomic-signature (gain of chromosome 7- EGFR gene, loss of chromosome 13- RB1 gene, loss of chromosome 10-PTEN gene); on the other, it is not obvious that the new identified CNAs are passenger mutations, as they may be necessary for tumor progression specific for the individual patient. Through our approach, we were able to demonstrate that not only individual genes into a pathway can be perturbed through multiple mechanisms and at different levels, but also that different combinations of perturbed genes can incapacitate functional modules within a cellular networks. Therefore, beyond the differences that can create apparent heterogeneity of alterations among GSC lines, there's a sort of selective force acting on them in order to converge towards the impairment of cell development and differentiation processes. This new overview could have a huge importance in therapy.

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The GSCs’ methylation profiles evidence the functional impairment of cell development and differentiation processes.(A) Functional annotation analysis of commonly methylated or unmethylated gene promoters in all the three GSC lines (GBM2, G144 and G166), performed using GOstat software. The graph shows the percentage (y-axis) of each category compared to totally annotated genes. (B) Top 10 pathways influenced by DNA methylation pattern in GSCs. A p-value (calculated by the Ingenuity Pathway Analysis, IPA, software) is associated to each pathway; this value represents the probability that such association could have occurred by chance.
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pone-0057462-g005: The GSCs’ methylation profiles evidence the functional impairment of cell development and differentiation processes.(A) Functional annotation analysis of commonly methylated or unmethylated gene promoters in all the three GSC lines (GBM2, G144 and G166), performed using GOstat software. The graph shows the percentage (y-axis) of each category compared to totally annotated genes. (B) Top 10 pathways influenced by DNA methylation pattern in GSCs. A p-value (calculated by the Ingenuity Pathway Analysis, IPA, software) is associated to each pathway; this value represents the probability that such association could have occurred by chance.

Mentions: Similarly, DNA methylation data were analyzed through these bioinformatic tools. Firstly, the analysis of gene promoters with the same methylation pattern among GSC lines showed an enrichment of terms related to the metabolism category, with a prevalence of unmethylated gene promoters (Figure 5A). Increased levels of unmethylation were found in other two categories: transcription & gene expression, which could lead to the activation of cancer-related genes, and in cell cycle, showing the de-regulation of cell proliferation in GSCs. On the other hand, GSCs showed a prevalence of methylated terms associated to development & morphogenesis and nervous system development & differentiation, showing an impairment of the developmental and differentiation processes. Cell death & apoptosis showed a balance between methylated and unmethylated gene promoters, thus epigenetic changes in these genes might act in order to maintain the malignant “homeostasis” of tumor cells. Conversely, four categories were involved only in unmethylated gene promoters (intracellular transport, DNA repair and chromatin remodeling, immune response and response to stress) perhaps increasing the potential malignant phenotype of GSCs. The analysis of gene promoters with the same methylation pattern among GSC lines through IPA software revealed the involvement of several cancer-related pathways (Figure 5B, Table S12). Curiously, two pathways had already been identified from the previous analysis of “exclusive” CNA regions (regulation of eIF4 and p70S6K signaling and ephrin receptor signaling), indicating that genomic and epigenomic alterations converge in the same direction.


Delineating the cytogenomic and epigenomic landscapes of glioma stem cell lines.

Baronchelli S, Bentivegna A, Redaelli S, Riva G, Butta V, Paoletta L, Isimbaldi G, Miozzo M, Tabano S, Daga A, Marubbi D, Cattaneo M, Biunno I, Dalprà L - PLoS ONE (2013)

The GSCs’ methylation profiles evidence the functional impairment of cell development and differentiation processes.(A) Functional annotation analysis of commonly methylated or unmethylated gene promoters in all the three GSC lines (GBM2, G144 and G166), performed using GOstat software. The graph shows the percentage (y-axis) of each category compared to totally annotated genes. (B) Top 10 pathways influenced by DNA methylation pattern in GSCs. A p-value (calculated by the Ingenuity Pathway Analysis, IPA, software) is associated to each pathway; this value represents the probability that such association could have occurred by chance.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585345&req=5

pone-0057462-g005: The GSCs’ methylation profiles evidence the functional impairment of cell development and differentiation processes.(A) Functional annotation analysis of commonly methylated or unmethylated gene promoters in all the three GSC lines (GBM2, G144 and G166), performed using GOstat software. The graph shows the percentage (y-axis) of each category compared to totally annotated genes. (B) Top 10 pathways influenced by DNA methylation pattern in GSCs. A p-value (calculated by the Ingenuity Pathway Analysis, IPA, software) is associated to each pathway; this value represents the probability that such association could have occurred by chance.
Mentions: Similarly, DNA methylation data were analyzed through these bioinformatic tools. Firstly, the analysis of gene promoters with the same methylation pattern among GSC lines showed an enrichment of terms related to the metabolism category, with a prevalence of unmethylated gene promoters (Figure 5A). Increased levels of unmethylation were found in other two categories: transcription & gene expression, which could lead to the activation of cancer-related genes, and in cell cycle, showing the de-regulation of cell proliferation in GSCs. On the other hand, GSCs showed a prevalence of methylated terms associated to development & morphogenesis and nervous system development & differentiation, showing an impairment of the developmental and differentiation processes. Cell death & apoptosis showed a balance between methylated and unmethylated gene promoters, thus epigenetic changes in these genes might act in order to maintain the malignant “homeostasis” of tumor cells. Conversely, four categories were involved only in unmethylated gene promoters (intracellular transport, DNA repair and chromatin remodeling, immune response and response to stress) perhaps increasing the potential malignant phenotype of GSCs. The analysis of gene promoters with the same methylation pattern among GSC lines through IPA software revealed the involvement of several cancer-related pathways (Figure 5B, Table S12). Curiously, two pathways had already been identified from the previous analysis of “exclusive” CNA regions (regulation of eIF4 and p70S6K signaling and ephrin receptor signaling), indicating that genomic and epigenomic alterations converge in the same direction.

Bottom Line: We found several canonical cytogenetic alterations associated with GBM and a common minimal deleted region (MDR) at 1p36.31, including CAMTA1 gene, a putative tumor suppressor gene, specific for the GSC population.Therefore, beyond the differences that can create apparent heterogeneity of alterations among GSC lines, there's a sort of selective force acting on them in order to converge towards the impairment of cell development and differentiation processes.This new overview could have a huge importance in therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery and Translational Medicine, University of Milan-Bicocca, Monza, Italy.

ABSTRACT
Glioblastoma multiforme (GBM), the most common and malignant type of glioma, is characterized by a poor prognosis and the lack of an effective treatment, which are due to a small sub-population of cells with stem-like properties, termed glioma stem cells (GSCs). The term "multiforme" describes the histological features of this tumor, that is, the cellular and morphological heterogeneity. At the molecular level multiple layers of alterations may reflect this heterogeneity providing together the driving force for tumor initiation and development. In order to decipher the common "signature" of the ancestral GSC population, we examined six already characterized GSC lines evaluating their cytogenomic and epigenomic profiles through a multilevel approach (conventional cytogenetic, FISH, aCGH, MeDIP-Chip and functional bioinformatic analysis). We found several canonical cytogenetic alterations associated with GBM and a common minimal deleted region (MDR) at 1p36.31, including CAMTA1 gene, a putative tumor suppressor gene, specific for the GSC population. Therefore, on one hand our data confirm a role of driver mutations for copy number alterations (CNAs) included in the GBM genomic-signature (gain of chromosome 7- EGFR gene, loss of chromosome 13- RB1 gene, loss of chromosome 10-PTEN gene); on the other, it is not obvious that the new identified CNAs are passenger mutations, as they may be necessary for tumor progression specific for the individual patient. Through our approach, we were able to demonstrate that not only individual genes into a pathway can be perturbed through multiple mechanisms and at different levels, but also that different combinations of perturbed genes can incapacitate functional modules within a cellular networks. Therefore, beyond the differences that can create apparent heterogeneity of alterations among GSC lines, there's a sort of selective force acting on them in order to converge towards the impairment of cell development and differentiation processes. This new overview could have a huge importance in therapy.

Show MeSH
Related in: MedlinePlus