Diffuse Gliomas of Human Adults part 1 · Dysembryoplastic neuroepith. tumor 0 Ganglioglioma 1...
Transcript of Diffuse Gliomas of Human Adults part 1 · Dysembryoplastic neuroepith. tumor 0 Ganglioglioma 1...
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Diffuse Gliomas of Human Adultspart 1
7. April 2009
Luigi Mariani Neurochirurgie
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WHO 2007: 132 Entities, Metastases excluded!
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Tumoren des Hirns„neuroepithelial“
Tumoren der Nerven
Tumoren der Hirnhäute„Meningen“
Tumore der Hypophysenregion„Hirnanhangdrüse“
Keimzelltumore
Blutzelltumore
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Symptome
Fokal:
“minus” an Funktion: Ausfall
“plus”: zB Epilepsie, Hormone
Hirndruck
“Zufall”: asymptomatisch
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Schmerzhafte Strukturen im/am KopfSchmerzhafte Strukturen im/am Kopf
Hirnhäute
AugenZahnwurzelnInnenohrRachenäussere Haut nach P. Duus, 1995
SchmerzprojektionSchmerzprojektion
Nebenhöhlen(Sinus)
Gefässe
??Kopfschmerzen: harmlos?
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World Cancer Report 2003
(Metastases excluded)
Grad I
�No Growth or over Years
�Well delimited
�Life expectancy usually not
reducedGrad III und IV
�Growth (weeks/months)
�Infiltration, Invasion
�Life expectancy reducedGrad II
�Growth over Months/Years
�Infiltration, Malignant transformation
�Life expectancy in danger
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Localization
Transformation / Proliferation
Infiltration / Invasion
WHO I
WHO II-IV
Prognosis
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1. Kinder
2. Erwachsene
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NeuroepithelialTumors
HypophysenadenomKraniopharyngeom
Neurinome(Schwannome) Meningeome
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Neuroepitheliale Tumoren� Astrocytic tumors� Diffuse astrocytoma 3*
fibrillary, protoplasmic, gemistocytic� Anaplastic astrocytoma 3� Glioblastoma 3
Giant cell glioblastoma 3Gliosarcoma 3
� Pilocytic astrocytoma 1� Pleomorphic xanthoastrocytoma 3� Subependymal giant cell astrocytoma 1�
� Oligodendroglial tumors� Oligodendroglioma 3� Anaplastic oligodendroglioma 3�
� Mixed gliomas� Oligoastrocytomas 3� Anaplastic oligoastrocytoma 3
� Ependymal tumors� Ependymoma 3� cellular, papillary, clear cell,
tanycytic� Anaplastic ependymoma 3� Myxopapillary ependymoma 1� Subependymoma 1�
� Choroid plexus tumors� Choroid plexus papilloma 0� Choroid plexus carcinoma 3
Glial tumors of uncertain originAstroblastoma 3Gliomatosis cerebri 3Chordoid tumor of the 3rd ventricle 1
Neuronal and mixed neuronal-glialtumorsGangliocytoma 0Dysplastic gangliocytoma of cerebellum
(Lhermitte-Duclos) 0Desmoplastic infantile astrocytoma/ganglioglioma
1Dysembryoplastic neuroepith. tumor 0Ganglioglioma 1Anaplastic ganglioglioma 3Central neurocytoma 1Cerebellar liponeurocytoma 1Paraganglioma of the filum terminale 1
Neuroblastic tumorsOlfactory neuroblastoma 3Olfactory neuroepithelioma 3Neuroblastoma of the adrenal glandand sympathetic nervous system 3
Pineal parenchymal tumorsPineocytoma 1Pineoblastoma 3Pineal parenchymal tumor of
intermediate differentiation 3
Embryonal tumorsMedulloepithelioma 3Ependymoblastoma 3Medulloblastoma 3
desmoplasticlarge cellMedullomyoblastomamelanotic
Supratentorial primitiveneuroectodermal tumor(PNET) 3
NeuroblastomaGanglioneuroblastoma
Atypical teratoid/rhabdoidtumor 3
*Behaviour:0 = benign;1 = low or uncertain malignancy3 = malignant
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Medulloblastoma
�Age peak <10years�Males>Females�Cerebellar vermis�Positive Prognostic Factors:
�Higher age�No dissemination�Total removal achieved�Expression of Neurotrophin Receptor TrkC*
�Negative Prognostic factor: myc Ampl.-Expr.�Survival at 5 years 50-75%, Side effects of ttt.�Cell of Origin:
Granular cell neurons cerebellum�Role of transcription factors in tumorigenesis**:
Olig2, Tlx3
*Segal und Pomeroy PNAS 1994, mRNA Northern; Grotzer JCO 2000, mRNA ISH)
** Schüller et al, 2007, transgenic mice
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Diffuse Gliomas (WHO 2007)
•Astrocytic tumors WHO grade•Diffuse astrocytoma (A) II
fibrillary, protoplasmic, gemistocytic•Anaplastic astrocytoma (AA) III•Glioblastoma (GBM) IV
Giant cell glioblastoma IVGliosarcoma IV
•Pilocytic astrocytoma I•Pleomorphic xanthoastrocytoma II•Subependymal giant cell astrocytoma I
•Oligodendroglial tumors WHO grade•Oligodendroglioma (O) II•Anaplastic oligodendroglioma (AO) III
•Mixed gliomas WHO grade•Oligoastrocytomas (OA) II•Anaplastic oligoastrocytoma (AOA) III
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Diffuse Gliome
Grad II Grad III Grad IV = Glioblastom
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Diffuse Gliome des Erwachsenen
WHO Grad2 Jahres-
Überleben (~)
Alter
(~)Relative
Häufigkeit (~)
II 85% 40 J 20%
III 70% 50 J 15%
IV
Glioblastom25% 60 J 65%
2JInselspital, Bern, 2007
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Ursachen
�Assoziert mit genetischen Krankheiten (selten)
�Ionisierende Strahlen (z.B. nach Radiotherapie)
�Häufigkeitsgipfel bei Kinder , dann wieder zunehmende Häufigkeit im Alter
�Geschlecht
�Rasse (kaukasisch weiss)
�Keine „moderne“ Erkrankung = „konstante“ Epidemiologie
�Keine „Noxen“ bekannt:
?
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Familiäre TumorsyndromeSyndromSyndromSyndromSyndrom GenGenGenGen ChromosomChromosomChromosomChromosom NervensystemNervensystemNervensystemNervensystem HautHautHautHaut Sonst. GewebeSonst. GewebeSonst. GewebeSonst. Gewebe
Neurofibromatose 1Neurofibromatose 1Neurofibromatose 1Neurofibromatose 1 NF1 17q11 Neurofibrom, MPNST, optisches Gliom, Astrozytom
Café-au-lait Flecken, axilläre Epheliden
Iris-Hamartome, ossäre Läsionen, Pheokromozytom, Leukämie
Neurofibromatose 2Neurofibromatose 2Neurofibromatose 2Neurofibromatose 2 NF2 22q12 Bilaterales Akustikusneurinom, peripheres Schwannom, Meningeom, Meningionangiomatose, spinales Ependymom, Astrozytom, gliales Hamartom, zerebrale Verkalkungen
- Linsentrübung, retinale Hamartome
Von HippelVon HippelVon HippelVon Hippel----LindauLindauLindauLindau----KrankheitKrankheitKrankheitKrankheit
VHL 3p25 Hämangioblastom - Retinale Hämangioblastome, Nierenzellkarzinom, Pheokromozytom, viszerale Zysten
TuberTuberTuberTuberööööse Hirnsklerosese Hirnsklerosese Hirnsklerosese Hirnsklerose(M. Bourneville)(M. Bourneville)(M. Bourneville)(M. Bourneville)
TSC1TSC2
9q3416p13
Subependymales Riesenzellastrozytom, „cortical tubers“
Kutane Angiofibrome (adenoma sebaceum), peau chagrin, subungueale Fibrome
Kardiales Rhabdomyom, Dünndarm-Polypen, Lungen-und Nierenzysten, Lymphangioleiomyomatose, Angiomyolipom der Niere
LiLiLiLi----FraumeniFraumeniFraumeniFraumeni----SyndromSyndromSyndromSyndrom TP53 17p13 Astrozytom, PNET - Mamma-Karzinom, Leukämie, Sarkom, adrenokortikales Karzinom
CowdenCowdenCowdenCowden----KrankheitKrankheitKrankheitKrankheit PTEN (MMAC1)
10q23 Dysplastisches Gangliocytom des Cerebellums (Lhermitte-Duclos), Megalenzephalie
Multiple Trichilemmome, Fibrome
Kolon-Polypen,, Schilddrüsentumore, Mamma-Karzinom
TurcotTurcotTurcotTurcot----SyndromSyndromSyndromSyndrom APChMLH1hPSM2
5q213p217p22
MedulloblastomGlioblastom Café-au-lait Flecken
Kolorektale-PolypenKolorektale-Polypen
Naevoid Basal Cell Naevoid Basal Cell Naevoid Basal Cell Naevoid Basal Cell Carcinoma syndrome Carcinoma syndrome Carcinoma syndrome Carcinoma syndrome (Gorlin)(Gorlin)(Gorlin)(Gorlin)
PTCH 9q31 Medulloblastom Multiple Basaliome, palmar and plantar pits
Unterkiefer-Zysten, Fibrome des Ovars, Skelettanomalien
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Neurofibromatose 1
Diagnostische Kriterien der NF1Diagnostische Kriterien der NF1Diagnostische Kriterien der NF1Diagnostische Kriterien der NF1Zwei oder mehr der folgenden Merkmale:Zwei oder mehr der folgenden Merkmale:Zwei oder mehr der folgenden Merkmale:Zwei oder mehr der folgenden Merkmale:
≥≥≥≥6 caf6 caf6 caf6 caféééé----auauauau----lait Flecken lait Flecken lait Flecken lait Flecken von >5 mm (prepubertär), resp. >15 mm Durchmesser (postpubertär)
≥≥≥≥2 Neurofibrome2 Neurofibrome2 Neurofibrome2 Neurofibrome, oder≥≥≥≥1 plexiformes Neurofibrom1 plexiformes Neurofibrom1 plexiformes Neurofibrom1 plexiformes Neurofibrom
AxillAxillAxillAxillääääre und/oder inguinale Ephelidenre und/oder inguinale Ephelidenre und/oder inguinale Ephelidenre und/oder inguinale Epheliden
Gliom des N. opticusGliom des N. opticusGliom des N. opticusGliom des N. opticus
OssOssOssOssääääre Lre Lre Lre Lääääsion sion sion sion (sphenoidale Dysplasie, Ausdünnung der kortikalis eines langen Knochen)
Verwandte/r ersten Grades mit NF1Verwandte/r ersten Grades mit NF1Verwandte/r ersten Grades mit NF1Verwandte/r ersten Grades mit NF1
Hauptmanifestationen der NF1Hauptmanifestationen der NF1Hauptmanifestationen der NF1Hauptmanifestationen der NF1
TumoralTumoralTumoralTumoral AndereAndereAndereAndere
Neurofibrome (dermal, nodulär, plexiform) Ossäre Läsion (Skoliose, Minderwuchs, Makrocephalie, Pseudarthrose, Dysplasie des Sphenoids)
Gliome (N. opticus, Astrozytom, Glioblastom)
Nervensystem (Minderintelligenz, Epilepsie, Neurophatie, Hydrocephalus (Aqueduktstenose)
Sarkome (Neurofibrosarkom, Rhabdomyosarkom, Triton-Tumor)
Vaskuläre Läsionen (Fibromuskuläre Hyperplasie (Nierenarterie)
Neuroendokrine Tumore (Pheochromozytom, Carcinoid-Tumor)
Hämatologische Tumore (juvenile CML)
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Treatment
1. Surgery (Resection, local Therapies)
2. Radiation
3. Antitumoral Drugs
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Glioblastoma multiforme
HE
GFAP
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Mikroneurochirurgie Navigation
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13j MädchenKomplex partielleAnfälle
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Optimierung der Chirurgischen Extirpation von Glioblastomen
„5-ALA directed“ surgery„white light“ surgery
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GBM resection
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Speech activation
The 4. Dimension: Function
Motor activation
Fibre connectionsDiffusor Tensor Imaging (Diffusion Weighted MRI)
Cortical areasFunctional MRI
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MRT im OP
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Stummer et al 2008
Role of Surgery for GBM
„komplette“ Extirpation
inkomplette Extirpation
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Stummer 2008
Role of Surgery in GBMKlinik für Neurochirurgie
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Infiltration von glialen Tumorzellen bei GBM
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Entfernung des proliferativen Tumorknotens ...
… es bleiben unzählige infiltrierende Tumorzellen in der Oedemzone
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Radiation
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Glioblastoma – Radiation therapyClass 1 evidence
From: Radiotherapy for newly diagnosed malignant glioma in adults: a systematic review. Laperriere et al, Radiotherapy and Oncology, 2002
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R. Stupp et al, NEJM 352(10):987-996, 2005
Progression-free Survival Overall Survival
Glioblastoma – ChemotherapyClass 1 evidence
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Alter und Genetische Tumor-Marker
Ohgaki al, NEJM 2007
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57 yo, GBMearly postop. MRI
5 months later despite radio-chemotherapy
Recurrence
80-90% of GBM recur within 2 cm from resection cavity!
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Invasion - Necroscopic evidence
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Preoconditions for more effective therapies
Local strategiesLocal control of proliferative bulkSurgery - Radiation – local drugsLow systemic and neurologic toxicity
Systemic strategiesControl of invasive cellsApoptosis inducing drugs through blood-brain-barrierLow systemic and neurologic toxicity
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Biology of Glioblastoma
�Tumorigenesis
�Invasion
�Models
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Zhu and Parada (2002), nature reviews 2; 616
Neurons
Oligodendrocytes
Astrocytes
Neuronal-restrictedprogenitor cells
Glial-restrictedprogenitor cells
Neural stem cells
Medulloblastoma
Oligodendroglioma
Oligoastrocytoma
Astrocytoma
Gliomas and Meduloblastomas – Cell of Origin?
NeuralProgenitorcells
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Glioblastoma - Cell of origin
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Primary GBM
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Primary GBM – Gain
Amplification
Double minute chrom.
Overexpressed in 70-90% of amplified cases. EGFR expression profile distinguishes different for more than 90 genes
EGFRvIII constitutively active in 20-50% of amplified cases
Proliferation/invasion/survival
PI3-kinase converting PIP2 to PIP3, activating AKT and mTOR (proliferation/survival)
RAS pathway
MAP-kinase pathways
Gain of 7
EGFR (7)
40% of GBM (not young patients)
GeneChrom
Genomics Transcriptomics / Proteomics / Signalling / Pathways
Catalytic subunit of PI3-kinase, activating AKTPIK3CA (Chrom 3q), Ampli. in 0-68% of GBM
Overexpression distinguishing 1. GBM from 2. GBM
Accumulation of IGFBP2 in GBM cells, Invasion
Dozens of genes (e.g. IGFBP2, IGFBP5)
Strong Overexpression leading to transcriptional activation of more than 100 genes
Induces transcription of VEGF, VEGFR, angiopoietin … (angiogenesis, vascular permeability, homing of lymphocytes)
carbonic anhydrase, LDH (cellular metabolism), BNIP (survival),c-met, CXCR4 (migration) …
Hypoxia master regulator HIF1α
Dozens of genes
MDM2 overexpressed in >50% of 1. GBM by IHC
MDM2 binds to mutant and wt p53 in autoregulatory loop and disrupts P53/MDM2/p14ARF pathway. Cell cycle, response to cell damage, cell death, cell differentiation, angiogenesis
Loss of activation of p53, thus loss of p21Waf1/Cip1
MDM2 (12q14.3-q15)
50% of 1. GBM
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Primary GBM – LossGeneChrom
Genomics
Mutations Loss of inhibition of PIP3 , thus activation of AKT and mTOR (proliferation/survival)
Loss of dephosphorylation of FAK (migration)
PTEN (Chr. 10q)
15-40% of GBM
Catalytic subunit of PI3-kinasePIK3CA (3q), Mutation <10-27% of GBM
Complete loss of 1 copy
LOH 10p14-p15 in 1.GBM
Unknown tumor suppressor genes
Loss of inhibition of PIP3 , thus activation of AKT and mTOR (proliferation/survival)
Loss of dephosphorylation of FAK (migration)
Chromosome 10
60-80% of GBM
(Loss containing the PTEN gene in 75-95%)
Homozygous deletions, promoter methylation
Underexpression p14ARF
p53/mdm2/p14ARF pathway cell cycle/response to cell damage/ celldeath / cell differentiation / angiogenesis
p14ARF
76% of GBM
Transcriptomics / Proteomics / Signalling / Pathways
LOH 1p 12-15% of 1. GBM
LOH 19q (19q13.3) 6% of 1.GBM
Mutations/Deletions p16INK4a
CDK4 amplification
Loss of 13q including RB1 locus in 38% of 2. GBM
Promoter methylation of RB1 in 43% in 2. GBM
p16INK4a/CDK4/RB1 pathway
Control of progression through G1 into S phase.
RB1 107 kDa, phosphorylated by CDK4/cyclinD1 complex to induce release of E2F, TF for G1 into S.
P16INK4a binds and inhibits CDK4/cyclinD1 complex
P16INK4a (9p.21)
CDK4 (12q13-14)
RB1 (13q14)
In 40-50% of GBM
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Genetic heterogeneity
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CGH and genetic groups of primary GBM
Gain 7Loss 10qEGFR ampPTEN mutp16INK4a del
No gain 7No loss 10No EGFR ampNo p53 mutNo PTEN mut
No gain 7Loss 10No EGFR ampNo p53 mutNo PTEN mut
Misra et al, Clin Can Res 2005
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EGFR
EGFR amplification and overexpression
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EGFR
PTEN loss
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p53 / mdm2 / p14ARF pathway
p16INK4a/CDK4/RB1 pathway
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Targeting of TK Receptors
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Anti-VEGF therapy for GBM recurrence:Bevacizumab (Avastine) + Camptothecin (Irinotecan)
61% respondersPFS 6 mos= 38 months!
Vredenburgh 2007
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EGFR~40% amplification and ~ 60% overexpression(chr. 7p12, double minute chromosomes)
~ 30% PTENmutation (10q24)
MDM2 <10% amplification and ~50% overexpression
30-40% p16deletionINK4A loss (9q26)
Signal transduction activation(migration, invasiveness, …)
Signal transduction activation(apoptosis resistance, …)
Disrupt p14ARF and p16INK4apathways (G1 to S transition)
Tumorigenesis: primary GBMM
ON
TH
SCell of origin
WHO Grade IV
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Diffuse Gliomas of Human Adultspart 2
7. April 2009
Luigi Mariani Neurochirurgie
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Gliom Grad II - Management?
�„... we do not know: which patients we should treat; when and how we should treat them.“
Edward Laws, Lausanne, 1987
Klinik für Neurochirurgie
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Diffuse Gliome des Erwachsenen
WHO Grad2 Jahres-
Überleben (~)
Alter
(~)Relative
Häufigkeit (~)
II 85% 40 J 20%
III 70% 50 J 15%
IV
Glioblastom25% 60 J 65%
2JInselspital, Bern, 2007
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Gliom WHO Grad II
Gesamtüberleben, in Monaten
% Ü
berle
bend
e
SEER Review, Cancer, 2006
Klinik für Neurochirurgie
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Role of Surgery?
Surgery
Biopsy
Klinik für Neurochirurgie
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1. Age <40 J
2. Diameter <6 cm
3. Unilateral
4. Oligodendroglial
5. No neurological deficit
Pignatti et al (EORTC), JCO 2002
Better Prognosis(1% significance level, multivariate analysis)
Score 0-5
Low-risk0-2
High-risk3-5
Surgery/Biopsy
watch treat
Prognostic Factors
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Oligodendroglial?
Claus, Cancer 2006
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Oligodendroglioma
0
0,2
0,4
0,6
0,8
1
1,2
0 50 100 150 200
Time after diagnosis (months)
Sur
viva
l
astrocytomas and oligoastrocytomas n=73
oligodendrogliomas n=6
p=0.02
E
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Oligoastrocytoma?
0
0,2
0,4
0,6
0,8
1
1,2
0 50 100 150 200
Time after diagnosis (months)
Sur
viva
l . others n=42
fibrillary astrocytomas n=37
p=0.03
F
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Copyright © American Society of Clinical Oncology
Mariani, L. et al. J Clin Oncol; 24:4758-4763 2006
Markers of microsatellite polymorphism used to dete ct loss of heterozygosity for 1p and 19q
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Prevalence of LOH 1p in LGG
0
5
10
15
20
25
30
35
40
Oligodendrogliom Oligoastrozytom Astrozytom
no LOH 1p
LOH 1p
100% 54% 16%
Klinik für Neurochirurgie
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Prevalenz von LOH 1p in LGG
0
5
10
15
20
25
30
35
40
LOH 1p no LOH 1p
Astrozytom
Oligoastrozytom
Oligodendrogliom
32%
36%
32%
Klinik für Neurochirurgie
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0
0,25
0,5
0,75
1
0 50 100 150 200
Time after diagnosis (months)
S
urvi
val
.
Astrocytomas with LOH 1p19q, n=6
Astrocytomas without LOH 1p19q, n=39
p=0.09
F
„Pure“ Astrocytoma and LOH 1pKlinik für Neurochirurgie
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0
0,25
0,5
0,75
1
0 50 100 150 200
Time after diagnosis (months)
Sur
viva
l .
LOH 1p 19q (+) n=17
LOH 1p 19q (-) n=49
p=0.003
A
0
0,25
0,5
0,75
1
0 50 100 150 200
Time after diagnosis (months)
Sur
viva
l .
1p36 (+) n=21
p=0.01
1p36 (-) n=46
B
0
0,25
0,5
0,75
1
0 50 100 150 200
Time after diagnosis (months)
Sur
viva
l .
19q13 (+) n=22
19q13 (-) n=42
p=0.002
C
LOH 1p/19q LOH 1p LOH 19q
LOH 1p und 19q – Overall survival
JCO 2006 Keine Chemotherapie!
Klinik für Neurochirurgie
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LOH 1p/19q – Overall Survival
LOH 1p und 19q
∅∅∅∅LOH 1p/19q
p < 0.01
Update 2007
0
0,25
0,5
0,75
1
0 50 100 150 200
Time after diagnosis (months)
Sur
viva
l .
LOH 1p 19q (+) n=17
LOH 1p 19q (-) n=49
p=0.003
A Klinik für Neurochirurgie
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LOH 1p/19q = Predictive Factor
November 2004 Februar 2006
Chemotherapie
Klinik für Neurochirurgie
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Neoadjuvant Chemotherapy
November 2003 Juni 2004 Dezember 2005
Chemotherapie Operation
Klinik für Neurochirurgie
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Epigenetic gene silencing by DNA methylation
DNA methylation is an important epigenetic mechanism of tumors to silence tumor suppressor genes
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Role of MGMT during chemotherapy with alkylating agents (unmethylated MGMT promoter)
XXGXXG
Alkyl
Alkyl
MGMT promoter unmethylated: chemotherapy
MGMT
promoter coding regiongenomic DNA
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Role of MGMT during chemotherapy with alkylating agents (unmethylated MGMT promoter)
XXGXXG
MGMT promoter unmethylated: chemotherapy
Alkyl
Alkyl
MGMT
promoter coding region
tumor
genomic DNA
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Role of MGMT during chemotherapy with alkylating agents (methylated MGMT promoter)
XXGXXG
MGMT promoter methylated: chemotherapy
Alkyl
Alkyl
MGMT
promoter coding region
tumor
genomic DNA
CH3CH3CH3
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Quantitative MSP assay
MGMT Promoter
methylation-positive
methylation-negative
PCR
HEX
FAM
2:1
Primer extension
2:1
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Linearity of the Assay
U87:PBMC
U87 = methylated PBMC = unmethylated
Signal ratio
1:5
1:1
5:1
360
1000
1600
1400
1600
400
1:4
1:1.6
4:1
methylated unmethylated
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M-Primer
U-Primer
U-Primer
Case 2: hypermethylated DNA (from FFPE tissue)
Qualitative analysis:
Quantitative analysis:M-Primer
Case 2 (PCR)
Case 2 (Extension)
U87:PBMC=1.1(Extension)
M-Primer U-Primer
methylated
methylated
unmethylated
unmethylated
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Results
Glioma type n %methylated %hypomethyl. % PCR failed %methyl. Lit
O+OA II 29 86% 21% (24%) 0% 60%
O+OA III 18 55% 6% (10%) 0% 80%
A II 19 37% 5% (14%) 0% 46%
A III 25 40% 12% (30%) 0% 50%
G IV 135 44% 17% (39%) 0% 45%
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Glioma type methylated LOH 1p no loss
O+OA II+III yes 74% (26/35) 26% (9/35)no 8% ( 1/12) 92% (11/12)
A II+III yes 15% ( 2/12) 85% (11/13)no 0% ( 0/28) 100% (28/28)
G IV yes 10% ( 4/39) 90% (35/39)no 4% ( 2/55) 96% 53/55)
Gliomas with unmethylated MGMT promoter rarely have a LOH 1p/19q
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MGMT promoter methylation: a predictive factor for chemosensitivity in glioblastoma patients?
Glioblastoma tumours analysed: 135(patients with chemotherapy)PCR failed: 0/135 (0%)No MGMT methylation: 76/135 (56%)Methylation-positive (qualitative): 59/135 (44%)Hypermethylated (quantitative): 36/135 (27%)Hypomethylated (quantitative): 23/135 (17%)Survival data available (dead patients): 36/135 (27%)
Median survival MGMT-positive (qualitative): 24.4 monthsMedian survival MGMT-negative (qualitative): 14.3 months
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Hegi M, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JEC, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT Gene
Silencing and Benefit from Temozolomide in Glioblastoma NEJM 352(10):997-1003, 2005
Gliom WHO IVTMZ und MGMT status
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Progression free survival
0 12 24 36 48 600
20
40
60
80
100
month
prop
ortio
n pr
ogre
ssio
n fr
ee (%
)
22 Patients with WHO Grade II Glioma
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water fall plot response at 6 month (LOH)
res
pon
se (
% c
hang
e in
tum
or v
olum
e)
LOH 1p19qLOH 1p
LOH 19qneg.not done
-60
-40
-20
0
20
40
60
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water fall plot best response (LOH)
-100
-50
0
50
max
imal
res
pon
se (%
cha
nge
in tu
mor
vol
ume)
LOH 1p19qLOH 1p
LOH 19qneg.not done
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res
pon
se (
% c
han
ge
in t
umo
r vo
lum
e)
MGMT promotor methylation (%)
p=0.012
Correlation response 6 month vs. MGMT
20 40 60 80 100
-60
-40
-20
0
20
40
60
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res
pon
se (
% c
han
ge
in t
umor
vo
lum
e)
MGMT promotor methylation (%)
p=0.045
Correlation best response vs. MGMT
10 20 30 40 50 60 70 80 90 100
-80
-60
-40
-20
0
20
40
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Grades 1-2 Grades 3-4Event No of
patients% No of
patients%
Blood/bone marrowAnemia 13 59Leucopenia 9 41 2 9Thrombocytopenia 3 14 5 23
LaboratoryALT/AST 1 5Bilirubin 2 9Glucose 6 27Hyponatremia 1 5Hypernatremia 5 23
GastrointestinalNausea / vomitting 14 64Constipation 9 41
OthersMucositis 2 9Rash / Desquamation 2 9
Table 2 Toxicity
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Number %No of patients 22GenderMale 13 59Female 9 41Age, yearsMedian 53Range 27-72HistologyOligodendroglioma 10 45Oligoastrozytoma 7 32Astrozytoma 5 23Prior SurgeryBiopsy only 15 68Subtotal resection 7 32Prior Radiotherapy 6 27Tumorvolume (cm3)Median 69,7Range 21-332SideLeft 14Right 7Right and left 1Tumor locationFrontal lobe 9 41Insula 1 5Temporal lobe 4 18Parietal lobe 8 36Clinical symptomsseizure 18 82aphasia 7 32cognitive deficiency 9 41paralysis 1 5vertigo 1 5KPS at start of treatmentMedian 0Range 0-2Cycles of TMZMedian 12Range 4-22TMZ regimen (pts)Day 1-5 22 100Dose dense 7 32
Table 1 Patient characteristics
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Malignant Progression of WHO Grade II gliomas
Grade II Grade III Grade IV = GBM
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1994 1995 1998 2002
Secondary GBM
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Secondary GBM – Gain
Amplification
Double minute chrom.
Overexpressed in 70-90% of amplified cases
EGFRvIII constitutively active in 20-50% of amplified cases
Proliferation/invasion
PI3-kinase converting PIP2 to PIP3, activating AKT and mTOR (proliferation/survival)
RAS pathway
MAP-kinase pathways
EGFR (Chr. 7)
8% of GBM
GeneChrom
Genomics
Strong Overexpression leading to transcriptional activation of more than 100 genes
Induces transcription of VEGF, VEGFR, angiopoietin … (angiogenesis, vascular permeability, homing of lymphocytes)
carbonic anhydrase, LDH (cellular metabolism)
BNIP (survival)
c-met, CXCR4 (migration)
…
Hypoxia master regulator HIF1α
Transcriptomics / Proteomics / Signalling / Pathways
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Secondary GBM – LossGeneChrom
Genomics
Mutations Loss of inhibition of PIP3 , thus activation of AKT and mTOR (proliferation/survival)
Loss of dephosphorylation of FAK (migration)
PTEN (Chr. 10q)
4% of 2. GBM
Mutations, hot spots codons 248 and 273
P53/MDM2/p14ARF pathway. Accumulation of p53 protein (ICH)
MDM2 binds to mutant and wt p53 in autoregulatory loop. Cell cycle, response to cell damage, cell death, cell differentiation, angiogenesis
Loss of activation of p53, thus loss of p21Waf1/Cip1
p53 (17p13.1)
65% of 2. GBM
LOH10q23-24
LOH 10q25-qter in 2. GBM, e.g. DMBT1, homozygous deletion in 13-38%)
Unknown tumor suppressor genes
Loss of inhibition of PIP3 , thus activation of AKT and mTOR (proliferation/survival)
Loss of dephosphorylation of FAK (migration)
Chromosome 10q
63% of 2. GBM
Mutations
Deletions p16INK4a
CDK4 amplification
Loss of 13q including RB1 locus in 38% of 2. GBM
Promoter methylation of RB1 in 43% in 2. GBM
p16INK4a/CDK4/RB1 pathway
Control of progression through G1 into S phase.
RB1 107 kDa, phosphorylated by CDK4/cyclinD1 complex to induce release of E2F, TF for G1 into S.
P16INK4a binds and inhibits CDK4/cyclinD1 complex
P16INK4a (9p.21)
CDK4 (12q13-14)
RB1 (13q14)
In 40-50% of GBM
Transcriptomics / Proteomics / Signalling / Pathways
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Tumor Progression
Grade IIPrecursor cell Grade IIIGrade IVSecondary GBM
PDGF-A/PDGFR-α ↗ (~ 60%) FGF2 ↗…
p53p53p53p53 mutation (17p13) (~ 60%)mutation (17p13) (~ 60%)mutation (17p13) (~ 60%)mutation (17p13) (~ 60%)17p loss (~ 60%) 22q13.3 loss (~ 30%) 1p/19q LOH (~ 50%)…
~60% 10q LOHCDK4 amplification (12q13)VEGF Overexpression~ 25% Rb alteration (13q13) (disrupts p16INK4A)pathway)~50% DCC loss of expression~5% PTEN mutat. (10q24)~8% EGFR amplification…
Time5 years in mean
9p21 LOH9p21 LOH9p21 LOH9p21 LOH
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Integrated genomic analysis of GBM
Parsons et al, Science 2008 321:1807-1812
20‘661 protein coding genes in 22 GBMs:-12 % with mutations of IDH1 gene-5 out of the 6 patients with secondary GBM had a mutated IDH 1:
position 395codon 132, G to AArg to His
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Original Article
IDH1 and IDH2 Mutations in Gliomas
Hai Yan, M.D., Ph.D., D. Williams Parsons, M.D., Ph.D., Genglin Jin, Ph.D., Roger McLendon, M.D., B. Ahmed Rasheed, Ph.D., Weishi Yuan, Ph.D., Ivan Kos, Ph.D.,
Ines Batinic-Haberle, Ph.D., Siân Jones, Ph.D., Gregory J. Riggins, M.D., Ph.D., Henry Friedman, M.D., Allan Friedman, M.D., David Reardon, M.D., James Herndon, Ph.D., Kenneth W. Kinzler, Ph.D., Victor E. Velculescu, M.D., Ph.D., Bert Vogelstein,
M.D., and Darell D. Bigner, M.D., Ph.D.
N Engl J MedVolume 360(8):765-773
February 19, 2009
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IDH1 and IDH2 Mutations in Human Gliomas
Yan H et al. N Engl J Med 2009;360:765-773
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Enzymatic Activity of Wild-Type and Mutant IDH1 and IDH2 Proteins
Yan H et al. N Engl J Med 2009;360:765-773
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Study Overview
• Isocitrate dehydrogenases, encoded by the IDH1 and IDH2 genes, catalyze the reduction of NADP+ to NADPH in the brain
• One or the other of these two genes was found to be mutated in 70% of 445 gliomas of World Health Organization grade II or III
• The mutations abolished the enzymatic activity of the IDH1 and IDH2 proteins
• The evidence suggests that mutation of an IDH gene is an early event in the development of gliomas
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Survival of Adult Patients with Malignant Gliomas w ith or without IDH Gene Mutations
Yan H et al. N Engl J Med 2009;360:765-773
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IDH1 and IDH2 somatic Mutations in Astrocytomas
Yan H et al, NEJM 2009Confirmed by Watanabe et al, AJP 2009
Grade IIPrecursor cell Grade IIIGrade IVSecondary GBM
Time5 years in mean
IDH1 mutation codon R132 or IDH2 mutation codon 172: 90%Among IDH1/2 mutated tumors:TP53 mutation 84%PTEN 0%EGFR 0%CDKN2A and CDKN2B 0%1p loss 5%
IDH1 mutation codon R132 orIDH2 mutation codon R172: 75%Among IDH1/2 mutated tumors:TP53 mutation 82%PTEN 0%EGFR 0%CDKN2A and CDKN2B 0%1p loss 5%
IDH1 mutation codon R132IDH2 mutation codon 172: 73%Among IDH1/2 mutated tumors:TP53 mutation 73%PTEN 0%EGFR 0%CDKN2A and CDKN2B 12%
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IDH1 and IDH2 Mutations in Oligodendroglial Tumors
Yan H et al, NEJM 2009Confirmed by Watanabe et al, AJP 2009
Grade IIPrecursor cell Grade III
IDH1 mutation codon R132 or IDH2 mutation codon 172: 85%Among IDH1/2 mutated tumors:TP53 mutation 21%PTEN 0%EGFR 0%CDKN2A and CDKN2B 5%1p/19q loss 78%
IDH1 mutation codon R132 orIDH2 mutation codon R172: 95%Among IDH1/2 mutated tumors:TP53 mutation 10%PTEN 0%EGFR 0%CDKN2A and CDKN2B 9%1p loss 90%
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Watanabe et al, AJP 2009
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Watanabe et al, AJP 2009
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IDH1 and IDH2 Mutations = early event in gliomagenesis
Yan H et al, NEJM 2009
Grade IIAstrocytomaOligodendrogliomaPrecursor cell
Grade IIIAstrocytomaOligodendroglioma
IDH 1 or 2 Mutation p53 Mutation (astrocytoma) orLOH 1p/19q (oligodendroglioma)
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IDH1 and IDH2 = isocitrate dehydrogenase
�Chromosome 2q33
�„Krebs` cycle“: Metabolic pathway converting carbohydrates, fats and proteins into carbon dioxide and water to generate energy
�Cytosolic enzyme
�Biology of mutated IDH in Grade II gliomas needs to be elucidated
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>80% IDH1 and IDH2 Mutations, function?~ 60% PDGF-Aor PDGFR-α overexpr., FGF2 overexpression (autocrineactivation of signal transd. pathways)
~ 60% p53mutation (17p13) (disrupts p14ARF pathways, inhibits apoptosis, promotesgenomic instability), ~ 60% 17ploss, ~ 30% 22q13.3loss, ~ 50% 19qLOH
10qLOH, CDK4 amplification (12q13), ~ 25% Rbalteration (13q13) (disrupts p16INK4Apathway), ~50% DCC loss of expression
~5% PTENmutat. (10q24) (enhanced AKT activity, Forkhead transcription, promoted survival)
WHO Grade II
WHO Grade III
WHO Grade IV
2-10 YE
AR
STumorigenesis: secondary GBM Cell of origin
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HW Zheng et al. Nature 455, 1129-1133 (2008) doi:10.1038/nature07443
p53 and Pten inactivation cooperate to induce high-grade malignant gliomas
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Thank you!
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Glioma cell motility - in vitro evidence
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ab
ab
ab
_ase
RTK growthfactors
ECM/myelin
LOSS OF:
NCAMN-Cadherin ?
DCCgap junctions
Cx-43
GAIN OF:GF / GFR
ECM / IntegrinsBEHAB
CD44SPARC
proteases
invasion
_ase
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Tumorbiopsat1 Patient
PixCell II LCMor Clones
Astrozytom Zellline
Differential Display / cDNA MicroArray
Tumorzentrum Invasive Zellen
UnbehandeltMigrations-Stimuliert
Genetik der Astrozytom-Invasion
Tumorbiopsate> 1 Patient
“nicht”invasive Tumore
Invasive Tumore
Kandidat-Gene/Gen-Sequenzen verantwortlich für den invasiven Phenotyp
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Identifizierung von invasiven Astrozytomzellen in gefrorenen Preparate
Unter 20x Vergrösserung.“Laser-capture”von Astrozytomzellen
Entfernung von dissezierten Astrozytomzellen
Mariani et al, Cancer Res
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RNA Differential Display
AP1-AP7 different arbitraryprimer used in combination with H-T(11)A oligo-dT primer
C- Tumor CoreR- Invasive Rim
Mariani et al, Cancer Res
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P311Ein neues Invasionsgen, das ausgeschaltet werden kann
Antisense [µM]
0 1 2 3 4 5
Cha
nne
l Pea
k Fl
uore
scen
ce
400
800
1200
1600
0 1 2 3 4 5 6
Nor
mal
ized
Cop
y N
umbe
r
0
100
200
300
400
500
600
0 1 2 3 4 5
Mig
ratio
n R
ate
(µm
/day
)
0
30
60
90
120
150
Mariani et al, Cancer Res
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Death Associated Protein 3 (Dap-3)
Ein Invasions- und Apoptosegen, das ausgeschaltet werden kann
No coating
Coating with ECM
Control CAM 1uM 24 hrs
Mariani, Clin Cancer Res
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Astrozytom Zellline G112
cDNA MicroArray
UnbehandeltMigrations-Stimuliert
Genetik der Astrozytom-Invasion
Kandidat-Gene/Gen-Sequenzen verantwortlich für den invasiven Phenotyp
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Mariani et al, J Neurooncol
Matrix-aktivierte Gliom-Migration
Mariani et al, J Neurooncol
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CD44
EGF, PDGF HGF/SF
ECM proteins
LPA
ankyrin
FAK
Rac
EGFR
CTGF
N-WASP IQGAP
Arp2/3
α-cateninβ-catenin
E-cadherin
tenascinC
integrins
GAP43
Nucleation of actin atmembrane
Stabilizationof adherensjunctions
PTPL1associatedRho GAP1
ROK
Adducin 3γγγγ
Moesin profilin
Corticalactin
network
Actinmembranelinkage
Actinpolymerization
stress fibers
Neuropilin 2
VEGF
Plexin 5FN-14
HA Osteopontin
Elastin
MSE 55
PAI-1
Cdc42
CIP 4
αγ
β
G proteins Caveolin 2
Syntaxin 1
paxillinAnnexin 1
Actin
Osteopontin
Caveolin 2
GPCRs
Ras
Rho
PLCγγγγ
EzrinRadixin
Up regulated
Down regulated
Mariani et al, J Neurooncol
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Cdc2
Cyclin B
Cdc2 Cyclin B
Cdc2
Cyclin ACDK2
P107E2F
G1 Phase
Mitosis
G2 PhaseS Phase
Rb
Rb
E2F
P
P
P
CDK 4/6
Cyclin D
P107E2F
CDK2Cyclin E
p16
Ras
TGF ββββ DNA damage,other insults
Bax
P53-independentapoptosis
P53-dependentapoptosis
Bcl-2
Free E2F*
ARF
MDM2
PCNA
p18
Myc
E2CUbiquitinCarrierProtein
p15
p21
p53
p27
Up regulated
Down regulated
Cyclin A,B
Free E2F*
Mariani et al, J Neurooncol
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Fas
Fas Ligand
FADD
Caspase-8
FAF
Sentrin
UBC9
Annexin
Activation of Downstream-Caspases
Caspase-3 Caspase-6 Caspase-7
TNF
TNFR-1
FADD
Caspase-8
RAIDD
Caspase-2
Cleavage of Death Substrate
Fragmentation of DNA
DNA repair
Cell cycleKinases
Structural proteins
PARPpRbMdm-2
MuMaPITSLREDNA-PkFAK
PAK2MEKK-1
lamin A,B
Nucleus
Caspase-1
RICKCARDIAK
RIP3
JNK
FLIP
PKCδδδδG-actin
presenilins
gelsolinfodrin
TRAF1/2
RIP
Topoisomerase
Bcl-x
Bcl-2
Baxbadbid
Caspase-9PKR
PKR inhibitor
ICAD / CAD
Up regulated
Down regulated
TNFRsuperfamily
NF κκκκB
Cyt-C
Apaf-1
Mariani et al, J Neurooncol
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Tumorbiopsat1 Patient
RNA-Amplifikation
cDNA Microarray (das Ganze Transkriptom!)
Tumorzentrum Invasive Zellen
Astrozytom Zellline G112
ParentalMigrations-Stimuliert
Genetik der Astrozytom-Invasion
Tumorbiopsate> 1 Patient
“nicht”invasive Tumore
Invasive Tumore
Kandidat-Gene/Gen-Sequenzen verantwortlich für den invasiven Phenotyp
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0.01
0.1
1
10
100EH
D3*
KIA
A05
13**
RY
R2*
PTPR
N2*
OPC
ML*
*EF
NB3
**BE
X1*
*A
TX
*BC
LW**
CA
SP7
KLK
6**
CH
N1*
*EM
AP2
**D
AP3
**D
TR
MEF
2CPY
K2*
*V
IMIG
FPB5
IGFP
B2M
T1L
microarray profile QRT-PCR profile white matter profile
Hoelzinger, Mariani et al, submitted
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Invasion gradient
HE Sampleholes
Serialsamples
Tumour core
Tumour close
Close rim
Far rim
Midway
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Gli o
ma
WH
O II
I(n
=2)
GliomaWHO IV
(n=5)
Glioblastoma(n=21)
Glio
ma
WH
O IV Oligo-
astro-cytoma (n=3)
Epileptogenicbrain(n=5)
Pilocytic Astrocytoma
(n=5)
GliomaWHO III
(n=5)
Anaplastic astrocytoma(n=11)
Glioma (WHO II )(n=10)
Low grade astrocytoma(n=10)
Foetaltissue(n=3),
Medullo-blastoma
(n=5)
Gliotic controls(n=7)
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Autotaxin (ATX)in autokrines, Motilitätstimulierendes Ligand, überexprimiert in invasiven Astrozytomzellen
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Differential Display / cDNA MicroArray
Tumorbiopsat1 Patient
PixCell II LCMor Clones
Astrozytom Zellline G112
Tumorzentrum Invasive Zellen
ParentalMigrations-Stimuliert
Genetik der Astrozytom-Invasion
Tumorbiopsate> 1 Patient
“nicht”invasive Tumore
Invasive Tumore
Kandidat-Gene/Gen-Sequenzen verantwortlich für den invasiven Phenotyp
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Genetik der Gliom-Invasion
Gewebe von“nicht” invasiven Tumoren
WHO Grad II
Kandidat-Gene/Gen-Sequenzen verantwortlich für den invasiven Phenotyp
cDNA Microarray
Gewebe voninvasiven TumorenWHO Grad II
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ab
ab
ab
_ase
RTK growthfactors
ECM/myelin
LOSS OF:
NCAMN-Cadherin ?
DCCgap junctions
Cx-43
GAIN OF:GF / GFR
ECM / IntegrinsBEHAB
CD44SPARC
proteases
invasion
_ase Autotaxin
Dap-3p311
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Inherited mutations in families at increased risk of glioma
Syndrome Gene name Function
Neurofibromatosis 1NF1 Cytoskeletal protein with GTPase-
activating protein (GAP) domain,
regulates RASNeurofibromatosis 2NF2 Member of ERM family with growth- inhibitory functionTuberous sclerosis TSC1, TSC2 mTOR pathway
Retinoblastoma RB1 cell cycle
Li-Fraumeni syndrome TP53 cell cycle, apoptosis
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Common chromosomal alterations in gliomas*
*array-based comparative genomic hybridizationSchwartzbaum et al. (2006), Nature clicical practice neurology 2; 494
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Predictive markers for chemotherapy?
Astrocytoma II
Astrocytoma III
Secondary glioblastoma
Primary glioblastoma
Oligodendroglioma II
Oligodendroglioma IIIT
umour progression
Tum
our progression
PDGFR overexp.
EGFR amplif.p16/p14ARF del
CDK4 ampl
TP53 mutation, 60%
MDM2 amplif.
PTEN mutation
LOH 1p and 19q
LOH 10q
LOH 10qMGMT methyl 40%
MGMT methyl 46%
MGMT methyl 50%
MGMT methyl 70%
MGMT methyl 60%
MGMT methyl 80%telomerase 60%
telomerase 20%
telomerase 40%
telomerase 100%
telomerase 100%
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In vivo Model of diffuse Glioma
Figure 1
Zheng et al, Nature, 2008, 455:1129-1133
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Implication of the MGMT promoter methylation status for chemotherapy (qualitative MSP)
• Glioblastoma patients with unmethylated MGMT do not significantly benefit from the addition of temozolomide to the standard treatment with radiation therapy.
• Patients with methylated MGMT promoter have a significantly longer progression-free and overall survival with the combination of radiation therapy and temozolomide.
• Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor
• Success rate of the methylation-specific PCR was 67% (n=307)
Esteller et al. (2003) N Engl J med 343, 1350Hegi et al. (2004) Clin Cancer Res 10, 1871Hegi et al. (2005) N Engl J med 352, 997
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A large number of tumors are heterogeneous forMGMT expression.
Hypomethylation of the MGMT promoter?
Biological relevance?
Establishment of a quantitative MGMT promoter methylation assay by primer extension (modification of the commonly used gel-based assay)
tumorchemotherapy
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MGMT-Promoter Methylation: a quantitative assay
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Bisulfite treatment of DNA and PCR
XXXCXXCXXCGXXCGXXCGCGXXXX
Bisulfite treatment
XXXUXXUXXCGXXCGXXCGUGXXXX
CH3 CH3 CH3
CH3 CH3 CH3
PCR
XXXTXXTXXCGXXCGXXCGTGXXXX
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Commonly used gel-based MSP assay
MGMT Promoter
Potential methylation sites (CpG islands)
290 bp
PCR 1
PCR 2
A Primer specific formethylated DNA
B Primer specific forunmethylated DNA
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Commonly used gel-based MSP assay
methylatedunmethylated
Hegi et al. (2005) N Engl J med 352, 997
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M-Primer
U-Primer
U-Primer
Case 1: unmethylated DNA (from FFPE tissue)
Qualitative analysis:
Quantitative analysis:
M-Primer
Case 1 (PCR)
Case 1 (Extension)
U87:PBMC=1:1(Extension)
M-Primer U-Primer
methylated
methylated
unmethylated
unmethylated
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M-Primer
U-Primer
U-Primer
Case 12: hypomethylated DNA (from FFPE tissue)
Qualitative analysis:
Quantitative analysis:
M-Primer
Case 12 (PCR)
Case 12 (Extension)
U87:PBMC=1.1(Extension)
M-Primer U-Primer
methylated
methylated
unmethylated
unmethylated
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Case 125: hypermethylated DNA (from FFPE tissue)
Qualitative PCR:
Nested PCR:
Case 125 (PCR)
Case 125 (Ext.)
M-Primer U-Primer
methylated unmethylated
Quantitative analysis:
U-PrimerM-Primer
M-Primer U-Primer
methylated unmethylated
methylated
Case 125 (nested PCR)
unmethylatedmethylated
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p53 mutation (17p13) (~60%) 17p loss (~ 60%) 22q13.3 loss (~ 30%) 1p/19q LOH (~ 50%)…
Grad II
Tumor Progression
Vorläufer-Zelle Grad III Grad IVSekundäres Glioblastom
IDH1 and IDH2 Mutation >70%P53 MutationPDGF-A/PDGFR-α ↗ (~ 60%) FGF2 ↗…
10q LOHCDK4 amplification (12q13)~ 25% Rb alteration (13q13) (disrupts p16INK4A)pathway)~50%DCC loss of expression~5% PTEN mutat. (10q24)…
Ohgaki et al, AJP 2009
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Grade II
Tumor Progression
Precursor cell Grade III Grade IVSecondary Glioblastoma
PDGF-A/PDGFR-α ↗ (~ 60%) FGF2 ↗…
p53p53p53p53 mutation (17p13) (~ 60%)mutation (17p13) (~ 60%)mutation (17p13) (~ 60%)mutation (17p13) (~ 60%)17p loss (~ 60%) 22q13.3 loss (~ 30%) 1p/19q LOH (~ 50%)…
~60% 10q LOHCDK4 amplification (12q13)VEGF Overexpression~ 25% Rb alteration (13q13) (disrupts p16INK4A)pathway)~50% DCC loss of expression~5% PTEN mutat. (10q24)~8% EGFR amplification…
Time4-5 years in mean
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HW Zheng et al. Nature 455, 1129-1133 (2008) doi:10.1038/nature07443
Attenuated Myc expression restores hGFAP-Cre+;p53lox/lox;Ptenlox/+ TNS differentiation potential and reducestumorigenic potential.
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HW Zheng et al. Nature 455, 1129-1133 (2008) doi:10.1038/nature07443
p53 and Pten coordinately regulate Myc protein level as well asNSC self-renewal and differentiation.
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HW Zheng et al. Nature 455, 1129-1133 (2008) doi:10.1038/nature07443
hGFAP-Cre+;p53lox/lox;Ptenlox/+ gliomas mirror key features ofhuman malignant gliomas.
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Summary of Genetic and Clinical Characteristics of Brain Tumors in the Study
Yan H et al. N Engl J Med 2009;360:765-773
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Frequency of Common Genetic
Alterations in Gliomas with
Mutated or Wild-Type IDH1 and
IDH2 Genes
Yan H et al. N Engl J Med 2009;360:765-773
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Conclusion
• Mutations of NADP+-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas