3 / 2437
07.11.2017
3
IDH 1/2 mutations
WilliamsParsonsetal,Science2008
13
• 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
NADP
Arginin 132 residue
Crystal structure
IDH mutations
Yanetal,NewEnglandJournalofMedicine2009
14
• IDH mutations implicated in the
pathogenesis of malignant gliomas
• Common in lower grade gliomas
• IDH mutant tumors are genetically &
clinically distinct
1p 19q deletion
15
CairncrossJGetal,JNatlCancer Inst. 1998
What is the major reason for the observed
discrepancy in chemotherapy sensitivity
between oligodendroglioma and
astrocytoma?
16
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
Brain tumor cells interconnect to a
functional and resistant networt
Osswaldetal,Nature2015
17
Oligodendrogliomas lack long ‘tumor microtubes‘ that enable
multicellular communication in astrocytomas
Tumor microtubes convey resistance to surgical
lesions and chemotherapy in gliomas
18
Weil etal,Neurooncology2017
Highly interconnected
astrocytic tumor cells are
more resistant to TMZ
treatment
TM high
Lesstumor
cell regression
Isolated tumor
cells(*)are
morelikelyto
die