IDH mutations in gliomas

BRYDEN DAWES

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IDH mutations in gliomas

© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)

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Why is IDH important?

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• 2008 exome sequencing (n =105)• IDH 1 mutations

• 5/6 secondary glioblastoma• 7/99 primary glioblastoma

• Improved prognosis 3.8yrs vs 1.1 yrs• Association with P53• No assoication with PTEN, RB1,

EGFR and NF1

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Why is IDH important?

© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)

• 2009

• IDH 1 and IDH 2 sequencing on Duke University Tumour Bank

• CNS tumours = 445, Non CNS tumours 494

• Associated mutations – TP53, 1p19q, PTEN, EGFR, CDKN2A

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Why is IDH important?

© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)

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Why is IDH important?

© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)

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Why is IDH important?

© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)

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Why is IDH important?

© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)

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What is isocitrate dehydrogenase?

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• Oxidative decarboxylation of isocitrate to α-ketoglutarate (αKG)

• Uses NADP + as a cofactor• 3 – forms – sequence similarity

• IDH 1• 2q33• Localises to cytosol and perioxomes

• IDH 2• 15q26• Localises to the mitochondria

• IDH 3• Evolutionary distinct• Localises to mitochondria• Involved in TCA cycle

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What is isocitrate dehydrogenase?

© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)

• Homodimeric enzymes with 2 active sites• Distinct domains• Each active site binds

• Isocitrate• NAPD +• Cation

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What is isocitrate dehydrogenase?

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• Cellular function

• Glucose regulation

• Lipid metabolism

• Source of NADPH

• Antioxidant

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IDH mutation

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• Occur in AML,

cholangiocarcinoma, melanoma

• Precede other genetic

alterations

• Missense substitutions

• Gain of function

• Reduces αKG to D-2-

hydroxyglutarate (D2HG)

• Consumes NAPDH

• D2HG acts as oncometabolite

• αKG structurally similar

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IDH mutation

© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)

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IDH mutation

© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)

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D2HG as an oncometabolite

© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)

• Structurally similar to αKG

• Inhibits many αKG dependent

dioxygenases

• Histone demethylase – effect on DNA

methylation

• TET – dysregulation of DNA

demethylation dynamic

• Increases H1F1a expression –

Increasing VEGF, EPO

• Inhibit normal differentiation

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Cellular metabolism and growth

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• αKG and NADPH essential component

of cellular metabolism

• Normal concentrations of αKG and kreb

cycle metabolites

• Increase in glutamonolysis

• Sensitive to inhibition of glutaminase /

GDH

• Increase GDH expression

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Glioma classification and prognosis

© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)

• Improved prognosis

• Chemosensitivity

• Strong association with CpG island

methylation phenotype (G-CIMP)

• G-CIMP genotype has increased

incidence MGMT methylation

• ATRX and TERT lead to increased

telomerase activity

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Glioma classification and prognosis

© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)

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Summary

© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)

• IDH mutant glioma genetically and biologically distinct from IDH wild

type glioma

• R132H most common mutation

• Missense substitution causing gain of function

• Reduces αKG to D2HG

• D2HG acts as oncometabolite through inhibition of αKG dependent

pathways

• Effects cellular metabolism