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These data will provide evidence for the genetic drivers of functional diversity in

subclonal populations on DIPG and point to the prioritisation of specific somatic

variants as relevant for therapeutic targeting versus those that may be functionally

redundant. This work will begin in the first 12 months, but will only be completed within

a proposed second year of this project.

Anticipated output

The ultimate aim of this work is to use our increased functional understanding of the

heterogeneity within DIPG to devise novel therapeutic strategies which aim to exploit

the evolutionary dynamics of these tumours. Functionally relevant mutations present

in all tumour cells may be predicted to be a more advantageous target than those

present only in selected subclones. By building up a phylogenetic tree of branching

evolution, we will identify these 'trunk' and 'branch' variants in the primary tumour16

,

and select functionally relevant mutations for which targeted agents are available for

future in vitro drug efficacy studies. Although the variants found only in subclonal

populations may not be thought of as driving the tumour as a whole, phenotypic

convergence may occur where distinct subclonal populations independently acquire

distinct mutations in the same gene 15,18

. We have preliminary evidence for this in

DIPG, where we have observed different regions of the same tumour to harbour one

or other activating PIK3CA mutations, an observation recapitulated in vitro, whereby

cells acquire a distinct mutation from that present in a subclone of the original tumour.

Thus these data will answer fundamental questions of how best to target the

evolutionary processes at play.

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