IDH mutations in glioma

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  1. 1. IDH mutations in gliomas BRYDEN DAWES
  2. 2. SECTION TITLE SUB HEADING IDH mutations in gliomas 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
  3. 3. 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
  4. 4. 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
  5. 5. SECTION TITLE SUB HEADING Why is IDH important? 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
  6. 6. SECTION TITLE SUB HEADING Why is IDH important? 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
  7. 7. SECTION TITLE SUB HEADING Why is IDH important? 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
  8. 8. SECTION TITLE SUB HEADING Why is IDH important? 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
  9. 9. SECTION TITLE SUB HEADING What is isocitrate dehydrogenase? 2015 Macquarie Neurosurgery - Confidential (Copyright Text) Oxidative decarboxylation of isocitrate to -ketoglutarate (KG) 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
  10. 10. 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
  11. 11. SECTION TITLE SUB HEADING What is isocitrate dehydrogenase? 2015 Macquarie Neurosurgery - Confidential (Copyright Text) Cellular function Glucose regulation Lipid metabolism Source of NADPH Antioxidant
  12. 12. 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 KG to D-2- hydroxyglutarate (D2HG) Consumes NAPDH D2HG acts as oncometabolite KG structurally similar
  13. 13. SECTION TITLE SUB HEADING IDH mutation 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
  14. 14. SECTION TITLE SUB HEADING IDH mutation 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
  15. 15. SECTION TITLE SUB HEADING D2HG as an oncometabolite 2015 Macquarie Neurosurgery - Confidential (Copyright Text) Structurally similar to KG Inhibits many KG dependent dioxygenases Histone demethylase effect on DNA methylation TET dysregulation of DNA demethylation dynamic Increases H1F1a expression Increasing VEGF, EPO Inhibit normal differentiation
  16. 16. SECTION TITLE SUB HEADING Cellular metabolism and growth 2015 Macquarie Neurosurgery - Confidential (Copyright Text) KG and NADPH essential component of cellular metabolism Normal concentrations of KG and kreb cycle metabolites Increase in glutamonolysis Sensitive to inhibition of glutaminase / GDH Increase GDH expression
  17. 17. 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
  18. 18. SECTION TITLE SUB HEADING Glioma classification and prognosis 2015 Macquarie Neurosurgery - Confidential (Copyright Text)
  19. 19. 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 KG to D2HG D2HG acts as oncometabolite through inhibition of KG dependent pathways Effects cellular metabolism