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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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GSC epigenetic signature.Epigenetic comparison between GSC, NSC and GBM FFPE tissue methylation profiles. The inner circle shows the 378 shared methylated genes in GSC lines, while the middle circle points out 37/378 genes that were unmethylated in NSC lines. The external circle displays the methylation status in GBM FFPE tissues. Note that 10 of the 37 specifically methylated genes in the GSC lines and unmethylated in foetal NSC lines were unmethylated in GBM FFPE tissues, representing the GSC epigenetic signature. The asterisk identifies 27 “cancer de novo methylated genes” in GSC and GBM FFPE tissues vs. foetal NSCs (see also Table S9A).
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pone-0057462-g003: GSC epigenetic signature.Epigenetic comparison between GSC, NSC and GBM FFPE tissue methylation profiles. The inner circle shows the 378 shared methylated genes in GSC lines, while the middle circle points out 37/378 genes that were unmethylated in NSC lines. The external circle displays the methylation status in GBM FFPE tissues. Note that 10 of the 37 specifically methylated genes in the GSC lines and unmethylated in foetal NSC lines were unmethylated in GBM FFPE tissues, representing the GSC epigenetic signature. The asterisk identifies 27 “cancer de novo methylated genes” in GSC and GBM FFPE tissues vs. foetal NSCs (see also Table S9A).

Mentions: As the methylation or unmethylation of promoters is associated to a specific biological effect (repressing or allowing transcription, respectively), whereas the methylation of other functional genomic regions remains controversial [44], [45], we deepened our analysis only for promoter regions. We investigated the methylation status of selected genes, whose hypermethylation is specifically associated to GBM: RASSF1A, CDKN2A, MGMT, RB1, CDH1 and EMP3 (Table S8) [46]. These genes showed a heterogeneous pattern of methylation among the GSC lines and were mainly methylated in the GBM FFPE tissues rather than in the GSC lines. Thus, in order to identify a “GSC-specifically methylated genes” signature we compared the CGI methylation status of GSC lines, GBM FFPE tissues and foetal NSC data. We identified 27 gene promoters methylated in all three GSC lines and FFPE GBM tissues and unmethylated in both the foetal NSC lines (Table S9A). Moreover, this comparison also pointed out 10 genes exclusively de novo methylated in GSC lines and not in GBM FFPE tissues related to NSCs, delineating a subgroup of genes exclusively methylated in GSCs (Figure 3 and Table S9B).


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)

GSC epigenetic signature.Epigenetic comparison between GSC, NSC and GBM FFPE tissue methylation profiles. The inner circle shows the 378 shared methylated genes in GSC lines, while the middle circle points out 37/378 genes that were unmethylated in NSC lines. The external circle displays the methylation status in GBM FFPE tissues. Note that 10 of the 37 specifically methylated genes in the GSC lines and unmethylated in foetal NSC lines were unmethylated in GBM FFPE tissues, representing the GSC epigenetic signature. The asterisk identifies 27 “cancer de novo methylated genes” in GSC and GBM FFPE tissues vs. foetal NSCs (see also Table S9A).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0057462-g003: GSC epigenetic signature.Epigenetic comparison between GSC, NSC and GBM FFPE tissue methylation profiles. The inner circle shows the 378 shared methylated genes in GSC lines, while the middle circle points out 37/378 genes that were unmethylated in NSC lines. The external circle displays the methylation status in GBM FFPE tissues. Note that 10 of the 37 specifically methylated genes in the GSC lines and unmethylated in foetal NSC lines were unmethylated in GBM FFPE tissues, representing the GSC epigenetic signature. The asterisk identifies 27 “cancer de novo methylated genes” in GSC and GBM FFPE tissues vs. foetal NSCs (see also Table S9A).
Mentions: As the methylation or unmethylation of promoters is associated to a specific biological effect (repressing or allowing transcription, respectively), whereas the methylation of other functional genomic regions remains controversial [44], [45], we deepened our analysis only for promoter regions. We investigated the methylation status of selected genes, whose hypermethylation is specifically associated to GBM: RASSF1A, CDKN2A, MGMT, RB1, CDH1 and EMP3 (Table S8) [46]. These genes showed a heterogeneous pattern of methylation among the GSC lines and were mainly methylated in the GBM FFPE tissues rather than in the GSC lines. Thus, in order to identify a “GSC-specifically methylated genes” signature we compared the CGI methylation status of GSC lines, GBM FFPE tissues and foetal NSC data. We identified 27 gene promoters methylated in all three GSC lines and FFPE GBM tissues and unmethylated in both the foetal NSC lines (Table S9A). Moreover, this comparison also pointed out 10 genes exclusively de novo methylated in GSC lines and not in GBM FFPE tissues related to NSCs, delineating a subgroup of genes exclusively methylated in GSCs (Figure 3 and Table S9B).

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