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Section 4: Description of Research Proposal

i. Original hypothesis

We and others have unequivocally proven that diffuse intrinsic pontine glioma (DIPG)

are biologically distinct from both paediatric and adult high grade glioma (HGG) arising

in other regions of the brain. With a restricted age of onset, unusual anatomical

location and different driving mutations, DIPG likely arise via unique evolutionary

processes which will require novel tailored therapeutics. By assessing the subclonal

architecture of DIPG and mapping the evolutionary dynamics across time and space,

we believe we can design more efficacious treatment strategies based on a

functionalising of the key subclonal variants present in the disease.

ii. Specific aims

To help us to understand and assign function to intratumoral genetic heterogeneity,

and to guide future treatment strategies in DIPG, we aim to answer two key questions:

- How does the subclonal architecture of DIPG differ across time and space?

- To what extent does genotypic heterogeneity confer phenotypic heterogeneity?

iii. Background and rationale

High grade gliomas (HGG) are tumours of the central nervous system that affect both

adults and children, and convey an extremely poor outcome. In children, median

survival is 12-15 months for cerebral hemispheric tumours (paediatric glioblastoma,

pGBM), and only 9-12 months for those arising in the brainstem (diffuse intrinsic

pontine glioma, DIPG)1. Whilst clinically and histologically similar, pGBM and DIPG

have unique underlying genetics, and represent distinct biological entities compared

with adult tumours2. A significant proportion of pGBM/DIPG are marked by specific

mutations in genes encoding the histone H3.3/H3.1 variants3,4, with a remarkable

degree of anatomical specificity and distinct clinicopathological characteristics5,6. In

addition, the spectra of secondary mutations differs in DIPG compared to paediatric

and adult GBM, and in many cases are unique, such as our recently discovered

mutations in ACVR1

7-9.

A major barrier to improving outcomes in HGG is their inherent intratumoral

heterogeneity, as evidenced by the phenotypic 'multiforme' nature of glioblastoma

cellular morphologies10

. We and others have shown that GBM in all ages and

locations are composed of multiple subclonal cell populations, marked in some cases

by mutually exclusive amplifications in genes encoding receptor tyrosine kinases11-13

.

These data have profound consequences for the development of efficacious targeted

therapies. Advances in sequencing technologies have provided unprecedented

insights into the diversity of cancer genomes, and have begun to reveal the genetic

complexity underpinning this intratumoral heterogeneity. In contrast to a linear model

of cancer evolution (with tumour progression based on a sequential development of

new mutations), many cancers seem to arise via a "branched evolution" model, with

shared genetic events present in ancestral clones ("trunk") driving initiation and

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