pediatric solid tumours

concepts of CSTs

maturation arrest
fewer mutations than adult tumours
behaviour dictated by microenvironment
common pathways - Wnt, SHH

ewing’s sarcoma

aberrant transcription driven by oncofusion that is necessary and sufficient for tumorigenesis
widespread activation of pathways

ewing’s tumour - chromosomal translocation

EWS-FLI1
EWS RNA binding Nt
FLI1 DNA binding Ct

targets of EWS-FLI1

wnt, IGF1, EGF, PDGF, FGF, VEGF
recruits BAF and disrupts TADs
BRCA1 inhibition

treatment targets of ewing’s tumour

EWS-FLI1
RNA helicase A target
HDACis and DNMTis

wilm’s tumour

disorganised and incomplete kidney development
aberrant metanephric development

genetic drivers of wilm’s tumour

LOH at 11p15 IGF-H19 gene cluster = loss of growth inhibition
WTX - wnt negative regulator
CTNB1 - beta catenin
WT1

WT1 structure

Nt protein interaction domain
Ct Zn finger domains
alternative splicing = 4 isoforms
with KTS = separation of Zn fingers, decreased DNA binding, increased RNA binding
without KTS = binds DNA and acts as a TF

kidney development and MET

condensed mesenchyme forms nephron via MET under control of wnt4

development of wilm’s tumour

arises from metanephric mesenchyme
normal growth restrictions are bypassed

function of WT1 in wilm’s tumour

acts as TSG
mutations = truncations
progenitor cells fail to differentiate

WT1 as an context dependent oncogene

ectopic expression without mutation in some AML subsets
inhibits E-cadherin = more EMT
promotes snail and slug TFs = inhibits E-cadherin = more EMT

familial neuroblastoma

GOF mutations in ALK are major cause
activated through kinase domain mutations or PHOX2B mutations

chromosomal rearrangements in neuroblastoma

can predict patient outcome
hyperploid tumours - increased survival rate
segmental alterations - more aggressive disease

neuroblastoma treatment

cyclopamine - SHH pathway antagonist
blocks proliferation of murine medulloblastoma cells and induces changes in gene expression - neuronal differentiation and loss of stemness