IDH mutations in glioma
-
Upload
mqlibrary -
Category
Health & Medicine
-
view
532 -
download
0
Transcript of IDH mutations in glioma
IDH mutations in gliomas
BRYDEN DAWES
SECTION TITLE
SUB HEADING
IDH mutations in gliomas
© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
SECTION TITLE
SUB HEADING
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
SECTION TITLE
SUB HEADING
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
SECTION TITLE
SUB HEADING
Why is IDH important?
© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
SECTION TITLE
SUB HEADING
Why is IDH important?
© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
SECTION TITLE
SUB HEADING
Why is IDH important?
© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
SECTION TITLE
SUB HEADING
Why is IDH important?
© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
SECTION TITLE
SUB HEADING
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
SECTION TITLE
SUB HEADING
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
SECTION TITLE
SUB HEADING
What is isocitrate dehydrogenase?
© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
• Cellular function
• Glucose regulation
• Lipid metabolism
• Source of NADPH
• Antioxidant
SECTION TITLE
SUB HEADING
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
SECTION TITLE
SUB HEADING
IDH mutation
© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
SECTION TITLE
SUB HEADING
IDH mutation
© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
SECTION TITLE
SUB HEADING
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
SECTION TITLE
SUB HEADING
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
SECTION TITLE
SUB HEADING
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
SECTION TITLE
SUB HEADING
Glioma classification and prognosis
© 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
SECTION TITLE
SUB HEADING
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