genetic and epigenetic basis of paediatric astrocytomas
TRANSCRIPT
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TheGene'candEpigene'cBasisofPaediatricAstrocytomas
Denise Sheer
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Overview
PaediatricbraintumoursLow-gradeastrocytomas
• MAPKac'va'on• Opportuni'esfortargetedtreatment• microRNAprofiling
High-gradegliomas• Chroma'naltera'ons• Subclassifica'on
Applica'onsofmolecularprofiling
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Cancerasadiseaseofthegenome
Genetic & Epigenetic alterations
Cancer Modified
gene expression
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Paediatricbraintumours
• Leadingcauseofcancer-relateddeathinchildren• Difficulttotreat
• Requireinterdisciplinarytherapeu'capproach• Survivorscanhavelong-termneurological,motor,hormonal,
&cogni'veimpairment
• Neuropathologymovedfrommorphology-basedapproachtouseofimmunohistochemical&molecularmarkers
• Biologystar'ngtobeunderstoodfrommolecularstudies
• Targetedtreatmentsemerging
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Grade I Pilocytic astrocytoma Grade II Diffuse astrocytoma Pilomyxoid astrocytoma Pleomorphic xanthoastrocytoma Grade III Anaplastic astrocytoma
Grade IV Glioblastoma
Paediatricastrocytomas
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Pilocytic astrocytoma • Most common paediatric brain tumour • Typically in cerebellum or midline
along hypothalamic/optic pathways • Well-circumscribed, non-invasive • Usually treated with surgery alone • Activated MAPK signalling Diffuse astrocytoma • Occur throughout the CNS • Infiltrating tumours • Difficult to remove with surgery alone • Treated with radiation and chemotherapy • Activated MAPK signalling • MYB mutations
Low-gradeastrocytomas
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KIAA1549-BRAF
Chr 7 KIAA1549 BRAF
Forshewetal,J.Pathol2009
BRAFgenefusionsinpilocy'castrocytoma
BRAFv600emuta'oninpilocy'canddiffuseastrocytoma
Ac'va'onsegmentofkinasedomain
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ExtracellularSignals
Activation of the MAPK pathway
RAF
MEK1/2
ERK1/2
RAS
Prolifera'onDifferen'a'onApoptosisMigra'onMetabolism
NF1
ReceptorTyrosineKinases
SenescenceinPilocy'c
Astrocytoma
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KIAA1549-BRAFBRAFv600eOtherBRAF/RAF1fusions
NF1-m FGFR1fusionsFGFR1TKDdupNTRK2fusions
Zhang et al, Nat Genetics 2013; Jones et al, Nat Genet 2013; Penman et al, Front Oncol 2015
Wholegenomesequencing
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Vemurafenib Dabrafenib
Sorafenib
Selumetinib
Perifosine
Perifosine MK2206
Rapamycin Everolimus
PI-103
KIAA1549-BRAFBRAFv600eOtherBRAF/RAF1fusions
NF1-m FGFR1fusionsFGFR1TKDdupNTRK2fusions
Zhang et al, Nat Genetics 2013; Jones et al, Nat Genet 2013; Penman et al, Front Oncol 2015
Opportuni'esfortargetedtherapy
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Karajannis, Neuro-Oncology 2014
AcceleratedtumourgrowthinSorafenibtrial!
NCT01338857 Sorafenib
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MicroRNAs in pilocytic astrocytomas modulate the MAPK and NF-kB pathways
RAF
MEK1/2
ERK1/2
RASNF1
ReceptorTyrosineKinases
IGFBP7
p16
CDK4CCND1
NF-kB
RBpathway
Senescence-AssociatedSecretoryPhenotype
Transcrip'onMYC,FOS,ETSCellcycle
CCND1Nega'vefeedback
SPRY,SPRED
miR-450b,miR-542-3p,miR-155
miR-34amiR-503 miR-34a
miR-155
miR-34a
miR-146amiR-224miR-155miR-199amiR-21
Jones,Jeyapalanetal,ActaNeuropathComm2015
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High-grade gliomas
• Highlymalignant,diffuselyinfiltra'ngtumours• Leadingcauseofcancer-relateddeathinchildren• 2-yearsurvival~12%• HistologysimilartoadultHGG• Molecularfounda'onsaredis'nctfromadultHGG
Paediatric GBM Young adult GBM Adult GBM
Adapted from Raabe et al, Cancer Cell 2012
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High-grade gliomas
Nucleosomalfibre
Corehistones
Essen'alCellBiology,Albertsetal,3rdEd.
Muta'onsinHistoneH3.3,ATRX&DAXX
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H3.3
H3.3isenrichedatregulatoryelements,promotersandac'vegenes
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TheATRX/DAXXcomplexloadsH3.3ontochroma'n
DAXXH3.3
ATRX
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Muta'onsinHistoneH3.3,ATRX&DAXX
Schwartzentruberetal,Nature2012
(H3.3)
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Muta'onsinHistoneH3.3Leadtoalteredgeneexpression
K27M G34R/V
Schwartzentruber et al, Nature 2012, Bjerke et al, Cancer Research 2013
MYCNGloballossofH3K27m3
Sequestra'onofPolycombEZH2
TP53mut
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Khuong-Quangetal,ActaNeuropathol2012
K27M-H3.3muta'onsaremoreprevalentinDIPG&areassociatedwithapoorprognosis
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Gajjar et al, JCO 2015
Dis'nctmolecularsubgroupsinpaediatrichigh-gradeglioma
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Molecularprofiling
Biology DiagnosisSub-classifica'on
Improvedclinicaltrials
PrognosisResponsetotherapy
Newtherapeu'capproaches
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Thanks to:
AmericanLebaneseSyrianAssociatedChari'es
Dr.ThomasJacques,DrAntonyMichalski,KimPhipps,Ins'tuteofChildHealth/GOSH,UCLProf.DavidEllison&Dr.RuthTatevossian,StJudeChildren’sResearchHospital,MemphisUSA
JennieJeyapalan
TaniaCorbek-Jones JohanAarum WilliamQays
Foster-HallNeilAtam