TheGene'candEpigene'cBasisofPaediatricAstrocytomas

Denise Sheer

Overview

PaediatricbraintumoursLow-gradeastrocytomas

• MAPKac'va'on• Opportuni'esfortargetedtreatment• microRNAprofiling

High-gradegliomas• Chroma'naltera'ons• Subclassifica'on

Applica'onsofmolecularprofiling

Cancerasadiseaseofthegenome

Genetic & Epigenetic alterations

Cancer Modified

gene expression

Paediatricbraintumours

•  Leadingcauseofcancer-relateddeathinchildren•  Difficulttotreat

•  Requireinterdisciplinarytherapeu'capproach•  Survivorscanhavelong-termneurological,motor,hormonal,

&cogni'veimpairment

•  Neuropathologymovedfrommorphology-basedapproachtouseofimmunohistochemical&molecularmarkers

•  Biologystar'ngtobeunderstoodfrommolecularstudies

•  Targetedtreatmentsemerging

Grade I Pilocytic astrocytoma Grade II Diffuse astrocytoma Pilomyxoid astrocytoma Pleomorphic xanthoastrocytoma Grade III Anaplastic astrocytoma

Grade IV Glioblastoma

Paediatricastrocytomas

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

KIAA1549-BRAF

Chr 7 KIAA1549 BRAF

Forshewetal,J.Pathol2009

BRAFgenefusionsinpilocy'castrocytoma

BRAFv600emuta'oninpilocy'canddiffuseastrocytoma

Ac'va'onsegmentofkinasedomain

ExtracellularSignals

Activation of the MAPK pathway

RAF

MEK1/2

ERK1/2

RAS

Prolifera'onDifferen'a'onApoptosisMigra'onMetabolism

NF1

ReceptorTyrosineKinases

SenescenceinPilocy'c

Astrocytoma

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

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

Karajannis, Neuro-Oncology 2014

AcceleratedtumourgrowthinSorafenibtrial!

NCT01338857 Sorafenib

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

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

High-grade gliomas

Nucleosomalfibre

Corehistones

Essen'alCellBiology,Albertsetal,3rdEd.

Muta'onsinHistoneH3.3,ATRX&DAXX

H3.3

H3.3isenrichedatregulatoryelements,promotersandac'vegenes

TheATRX/DAXXcomplexloadsH3.3ontochroma'n

DAXXH3.3

ATRX

Muta'onsinHistoneH3.3,ATRX&DAXX

Schwartzentruberetal,Nature2012

(H3.3)

Muta'onsinHistoneH3.3Leadtoalteredgeneexpression

K27M G34R/V

Schwartzentruber et al, Nature 2012, Bjerke et al, Cancer Research 2013

MYCNGloballossofH3K27m3

Sequestra'onofPolycombEZH2

TP53mut

Khuong-Quangetal,ActaNeuropathol2012

K27M-H3.3muta'onsaremoreprevalentinDIPG&areassociatedwithapoorprognosis

Gajjar et al, JCO 2015

Dis'nctmolecularsubgroupsinpaediatrichigh-gradeglioma

Molecularprofiling

Biology DiagnosisSub-classifica'on

Improvedclinicaltrials

PrognosisResponsetotherapy

Newtherapeu'capproaches

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