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Pathology, Molecular Genetics, and Epigenetics of Diffuse Intrinsic Pontine Glioma.

Buczkowicz P, Hawkins C - Front Oncol (2015)

Bottom Line: Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain cancer with no effective therapy.This review describes the most common molecular genetic and epigenetic signatures of DIPG in the context of molecular subgroups and histopathological diagnosis, including this tumor entity's unique mutational landscape, copy number alterations, and structural variants, as well as epigenetic changes on the global DNA and histone levels.The increased knowledge of DIPG biology and histopathology has opened doors to new diagnostic and therapeutic avenues.

View Article: PubMed Central - PubMed

Affiliation: Division of Pathology, The Hospital for Sick Children , Toronto, ON , Canada ; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children , Toronto, ON , Canada.

ABSTRACT
Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain cancer with no effective therapy. Histological similarity of DIPG to supratentorial high-grade astrocytomas of adults has led to assumptions that these entities possess similar underlying molecular properties and therefore similar therapeutic responses to standard therapies. The failure of all clinical trials in the last 30 years to improve DIPG patient outcome has suggested otherwise. Recent studies employing next-generation sequencing and microarray technologies have provided a breadth of evidence highlighting the unique molecular genetics and epigenetics of this cancer, distinguishing it from both adult and pediatric cerebral high-grade astrocytomas. This review describes the most common molecular genetic and epigenetic signatures of DIPG in the context of molecular subgroups and histopathological diagnosis, including this tumor entity's unique mutational landscape, copy number alterations, and structural variants, as well as epigenetic changes on the global DNA and histone levels. The increased knowledge of DIPG biology and histopathology has opened doors to new diagnostic and therapeutic avenues.

No MeSH data available.


Related in: MedlinePlus

Schematic of residue alterations in (A) histone H3, (B) TP53, (C) PPM1D, and (D) ACVR1 as a result of mutations most frequently identified in DIPG. GD, globular domain; TD, transactivation domain; OD, oligomerization domain; BD, basic domain; CID, CHEK1 interacting domain; GSD, GS domain; PKD, protein Kinase domain. Red indicates most frequently altered amino acid.
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Figure 1: Schematic of residue alterations in (A) histone H3, (B) TP53, (C) PPM1D, and (D) ACVR1 as a result of mutations most frequently identified in DIPG. GD, globular domain; TD, transactivation domain; OD, oligomerization domain; BD, basic domain; CID, CHEK1 interacting domain; GSD, GS domain; PKD, protein Kinase domain. Red indicates most frequently altered amino acid.

Mentions: The first major breakthrough in defining the DIPG mutational landscape came in 2012, when studies on pediatric brain tumors using whole-genome and WES reported that 70–84% of DIPG possess mutations in histone H3, and that these mutations were predictive of outcome (3, 24, 25). These recurrent mutations, in H3F3A or HIST1H3B/C/I (Figure 1A), result in a p. Lys27Met (K27M) substitution. A subset of other midline astrocytomas, such as those arising in the thalamus, have also been found to harbor K27M histone H3 mutations although at a lower frequency (50). Conversely, pediatric supratentorial HGA rarely possess these mutations, and more frequently have p. Gly34Arg (G34R) or p. Gly34Val (G34V) substitution in histone H3.3. The G34R/V-H3.3 mutations occur in 10–19% of supratentorial HGA cases (24) and are never found in DIPG (3). Furthermore, among supratentorial GBM, these G34R/V-H3.3 mutations are predominantly found in older children and young adults (3). Mutations affecting these two histone residues are extremely rare in adult HGA.


Pathology, Molecular Genetics, and Epigenetics of Diffuse Intrinsic Pontine Glioma.

Buczkowicz P, Hawkins C - Front Oncol (2015)

Schematic of residue alterations in (A) histone H3, (B) TP53, (C) PPM1D, and (D) ACVR1 as a result of mutations most frequently identified in DIPG. GD, globular domain; TD, transactivation domain; OD, oligomerization domain; BD, basic domain; CID, CHEK1 interacting domain; GSD, GS domain; PKD, protein Kinase domain. Red indicates most frequently altered amino acid.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4485076&req=5

Figure 1: Schematic of residue alterations in (A) histone H3, (B) TP53, (C) PPM1D, and (D) ACVR1 as a result of mutations most frequently identified in DIPG. GD, globular domain; TD, transactivation domain; OD, oligomerization domain; BD, basic domain; CID, CHEK1 interacting domain; GSD, GS domain; PKD, protein Kinase domain. Red indicates most frequently altered amino acid.
Mentions: The first major breakthrough in defining the DIPG mutational landscape came in 2012, when studies on pediatric brain tumors using whole-genome and WES reported that 70–84% of DIPG possess mutations in histone H3, and that these mutations were predictive of outcome (3, 24, 25). These recurrent mutations, in H3F3A or HIST1H3B/C/I (Figure 1A), result in a p. Lys27Met (K27M) substitution. A subset of other midline astrocytomas, such as those arising in the thalamus, have also been found to harbor K27M histone H3 mutations although at a lower frequency (50). Conversely, pediatric supratentorial HGA rarely possess these mutations, and more frequently have p. Gly34Arg (G34R) or p. Gly34Val (G34V) substitution in histone H3.3. The G34R/V-H3.3 mutations occur in 10–19% of supratentorial HGA cases (24) and are never found in DIPG (3). Furthermore, among supratentorial GBM, these G34R/V-H3.3 mutations are predominantly found in older children and young adults (3). Mutations affecting these two histone residues are extremely rare in adult HGA.

Bottom Line: Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain cancer with no effective therapy.This review describes the most common molecular genetic and epigenetic signatures of DIPG in the context of molecular subgroups and histopathological diagnosis, including this tumor entity's unique mutational landscape, copy number alterations, and structural variants, as well as epigenetic changes on the global DNA and histone levels.The increased knowledge of DIPG biology and histopathology has opened doors to new diagnostic and therapeutic avenues.

View Article: PubMed Central - PubMed

Affiliation: Division of Pathology, The Hospital for Sick Children , Toronto, ON , Canada ; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children , Toronto, ON , Canada.

ABSTRACT
Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain cancer with no effective therapy. Histological similarity of DIPG to supratentorial high-grade astrocytomas of adults has led to assumptions that these entities possess similar underlying molecular properties and therefore similar therapeutic responses to standard therapies. The failure of all clinical trials in the last 30 years to improve DIPG patient outcome has suggested otherwise. Recent studies employing next-generation sequencing and microarray technologies have provided a breadth of evidence highlighting the unique molecular genetics and epigenetics of this cancer, distinguishing it from both adult and pediatric cerebral high-grade astrocytomas. This review describes the most common molecular genetic and epigenetic signatures of DIPG in the context of molecular subgroups and histopathological diagnosis, including this tumor entity's unique mutational landscape, copy number alterations, and structural variants, as well as epigenetic changes on the global DNA and histone levels. The increased knowledge of DIPG biology and histopathology has opened doors to new diagnostic and therapeutic avenues.

No MeSH data available.


Related in: MedlinePlus