Brain 17 Vienna
07.11.2017
IDH 1/2 mutations
IDH mutations
Arginin 132 residue
NADP
Crystal structure
• IDH mutations implicated in the pathogenesis of malignant gliomas
• Recurrent mutations in IDH1 on chromosome 2q33 found in glioblastoma • IDH1 encodes isocitrate dehydrogenase 1 that catalyzes the oxidative carboxylation of isocitrate to alpha-ketoglutarate resulting in the production of NADPH • Novel marker for secondary glioblastoma
• Common in lower grade gliomas
• IDH mutant tumors are genetically & clinically distinct
WilliamsParsonsetal,Science2008
Yanetal,NewEnglandJournalofMedicine2009
13
14
1p 19q deletion
What is the major reason for the observed discrepancy in chemotherapy sensitivity between oligodendroglioma and astrocytoma?
A1. Astrocytic cells show a higher number of multidrug resistant- associatedABC transporters
A2. Chromosome 1 encodes the temozolomide-resistance gene zinc finger protein C2H2
A3. Astrocytic cells communicate more efficiently in cellular networks
A4. Oligodendroglial cells show impaired mitochondrial metabolism
A3 is correct
CairncrossJGetal,JNatlCancer Inst. 1998
15
16
Brain tumor cells interconnect to a functional and resistant networt
Tumor microtubes convey resistance to surgical lesions and chemotherapy in gliomas
TM high
Highly interconnected astrocytic tumor cells are more resistant to TMZ treatment
Lesstumor cell regression
Isolated tumor cells(*)are morelikelyto die
Oligodendrogliomas lack long ‘tumor microtubes‘ that enable multicellular communication in astrocytomas
Osswaldetal,Nature2015
Weil etal,Neurooncology2017
17
18
3
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