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

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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

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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

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