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Epigenetic dysregulation in glioma.

Kondo Y, Katsushima K, Ohka F, Natsume A, Shinjo K - Cancer Sci. (2014)

Bottom Line: Recent genome-wide genomic and epigenomic analyses have revealed that mutations in epigenetic modifiers occur frequently in gliomas and that dysregulation of epigenetic mechanisms is closely associated with glioma formation.Given that epigenetic changes are reversible, understanding the epigenetic abnormalities that arise in gliomagenesis might be key to developing more effective treatment strategies for glioma.In this review, we focus on the recent advancements in epigenetic research with respect to gliomas, consider how epigenetic mechanisms dynamically regulate tumor cells, including the cancer stem cell population, and discuss perspectives and challenges for glioma treatment in the near future.

View Article: PubMed Central - PubMed

ABSTRACT
Given that treatment options for patients with glioblastoma are limited, much effort has been made to clarify the underlying mechanisms of gliomagenesis. Recent genome-wide genomic and epigenomic analyses have revealed that mutations in epigenetic modifiers occur frequently in gliomas and that dysregulation of epigenetic mechanisms is closely associated with glioma formation. Given that epigenetic changes are reversible, understanding the epigenetic abnormalities that arise in gliomagenesis might be key to developing more effective treatment strategies for glioma. In this review, we focus on the recent advancements in epigenetic research with respect to gliomas, consider how epigenetic mechanisms dynamically regulate tumor cells, including the cancer stem cell population, and discuss perspectives and challenges for glioma treatment in the near future.

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Genetic and epigenetic alterations in gliomas. TP53, IDH1 and ATRX are frequently mutated in low-grade gliomas and secondary GBM. Mutation of IDH1 leads to aberrant DNA methylation, whereas mutations in the important chromatin modifier ATRX affect chromatin structure. In pediatric GBM, mutations in H3F3A and ATRX are found frequently and associated closely with gliomagenesis.
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fig01: Genetic and epigenetic alterations in gliomas. TP53, IDH1 and ATRX are frequently mutated in low-grade gliomas and secondary GBM. Mutation of IDH1 leads to aberrant DNA methylation, whereas mutations in the important chromatin modifier ATRX affect chromatin structure. In pediatric GBM, mutations in H3F3A and ATRX are found frequently and associated closely with gliomagenesis.

Mentions: Alongside known genetic changes, aberrant epigenetic alterations have emerged as common hallmarks of many cancers, including glioblastoma.(3) Recent large-scale genomic and epigenomic profiling studies, such as The Cancer Genome Atlas, have yielded novel data and deeper insight into gliomagenesis.(4) One surprising discovery is the identification of a large number of inactivating mutations in genes that control the epigenome (Fig. 1). Exome sequencing studies of 291 GBM revealed that 46% of cases had at least one somatic mutation in genes associated with chromatin modification. The genes included those associated with DNA methylation (isocitrate dehydrogenase [IDH] 1, IDH2), histone modification (mixed lineage leukaemia 2 [MLL2], MLL3, MLL4, Enhancer of zeste 2 [EZH2] and histone deacetylase 2 [HDAC2]) and chromatin remodeling (a-thalassaemia/mental retardation syndrome X-linked [ATRX], death-domain associated protein [DAXX], CREB binding protein [CREBBP] and SWI/SNF-related matrix-associated, actin-dependent regulator of chromatin A2 [SMARCA2]).(5) These mutations result in the impairment of DNA methylation, histone modification and nucleosome positioning, and are associated with aberrant gene expression.(6) For instance, a subset of gliomas, normally low-grade gliomas or secondary high-grade gliomas (proneural type), are characterized by both mutations in IDH1 or IDH2 and hypermethylation of DNA. This subset is referred to as glioma CpG island methylator phenotype (G-CIMP).(4) Hence, clarification of the crosstalk between the genome and epigenome might suggest new molecular targets and possibilities for the treatment of GBM.


Epigenetic dysregulation in glioma.

Kondo Y, Katsushima K, Ohka F, Natsume A, Shinjo K - Cancer Sci. (2014)

Genetic and epigenetic alterations in gliomas. TP53, IDH1 and ATRX are frequently mutated in low-grade gliomas and secondary GBM. Mutation of IDH1 leads to aberrant DNA methylation, whereas mutations in the important chromatin modifier ATRX affect chromatin structure. In pediatric GBM, mutations in H3F3A and ATRX are found frequently and associated closely with gliomagenesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317798&req=5

fig01: Genetic and epigenetic alterations in gliomas. TP53, IDH1 and ATRX are frequently mutated in low-grade gliomas and secondary GBM. Mutation of IDH1 leads to aberrant DNA methylation, whereas mutations in the important chromatin modifier ATRX affect chromatin structure. In pediatric GBM, mutations in H3F3A and ATRX are found frequently and associated closely with gliomagenesis.
Mentions: Alongside known genetic changes, aberrant epigenetic alterations have emerged as common hallmarks of many cancers, including glioblastoma.(3) Recent large-scale genomic and epigenomic profiling studies, such as The Cancer Genome Atlas, have yielded novel data and deeper insight into gliomagenesis.(4) One surprising discovery is the identification of a large number of inactivating mutations in genes that control the epigenome (Fig. 1). Exome sequencing studies of 291 GBM revealed that 46% of cases had at least one somatic mutation in genes associated with chromatin modification. The genes included those associated with DNA methylation (isocitrate dehydrogenase [IDH] 1, IDH2), histone modification (mixed lineage leukaemia 2 [MLL2], MLL3, MLL4, Enhancer of zeste 2 [EZH2] and histone deacetylase 2 [HDAC2]) and chromatin remodeling (a-thalassaemia/mental retardation syndrome X-linked [ATRX], death-domain associated protein [DAXX], CREB binding protein [CREBBP] and SWI/SNF-related matrix-associated, actin-dependent regulator of chromatin A2 [SMARCA2]).(5) These mutations result in the impairment of DNA methylation, histone modification and nucleosome positioning, and are associated with aberrant gene expression.(6) For instance, a subset of gliomas, normally low-grade gliomas or secondary high-grade gliomas (proneural type), are characterized by both mutations in IDH1 or IDH2 and hypermethylation of DNA. This subset is referred to as glioma CpG island methylator phenotype (G-CIMP).(4) Hence, clarification of the crosstalk between the genome and epigenome might suggest new molecular targets and possibilities for the treatment of GBM.

Bottom Line: Recent genome-wide genomic and epigenomic analyses have revealed that mutations in epigenetic modifiers occur frequently in gliomas and that dysregulation of epigenetic mechanisms is closely associated with glioma formation.Given that epigenetic changes are reversible, understanding the epigenetic abnormalities that arise in gliomagenesis might be key to developing more effective treatment strategies for glioma.In this review, we focus on the recent advancements in epigenetic research with respect to gliomas, consider how epigenetic mechanisms dynamically regulate tumor cells, including the cancer stem cell population, and discuss perspectives and challenges for glioma treatment in the near future.

View Article: PubMed Central - PubMed

ABSTRACT
Given that treatment options for patients with glioblastoma are limited, much effort has been made to clarify the underlying mechanisms of gliomagenesis. Recent genome-wide genomic and epigenomic analyses have revealed that mutations in epigenetic modifiers occur frequently in gliomas and that dysregulation of epigenetic mechanisms is closely associated with glioma formation. Given that epigenetic changes are reversible, understanding the epigenetic abnormalities that arise in gliomagenesis might be key to developing more effective treatment strategies for glioma. In this review, we focus on the recent advancements in epigenetic research with respect to gliomas, consider how epigenetic mechanisms dynamically regulate tumor cells, including the cancer stem cell population, and discuss perspectives and challenges for glioma treatment in the near future.

Show MeSH
Related in: MedlinePlus