IDH mutations in glioma

1. 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?
© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
• 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?
© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
• 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?
© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
• Cellular function
• Glucose regulation
• Lipid metabolism
• Source of NADPH
• Antioxidant

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IDH mutation
© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
• 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
© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
• 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