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carried out by the ICR's Tumour Profiling Unit (TPU) as part of an ongoing programme

within the Jones lab, expanded to incorporate advanced sampling. Somatic variants

will be called using the GATK best practise model after sequence alignment and

filtering, with support from a Senior Bioinformatics Officer within the Jones' lab.

Subclonal diversity will be assessed by integrating copy number profiles from an

orthogonal platform (Illumina 450K methylation arrays) and plotting the corrected

variant allele fractions, giving a measure of the subclonal fraction of tumour cells

carrying each variant. We have evidence from genome sequencing studies for

multiple dominant subclones in DIPG (Figure 1).

Figure 1 - Intratumoral heterogeneity in diffuse intrinsic pontine glioma. (a) Circos plot representing

whole genome sequencing of the primary tumour DIPG101. Somatic mutations are labelled on the

outer ring, with copy number changes (red = gain, blue = loss) on the inner rings. Structural variants

(green = intrachromosomal, orange = interchromosomal) are represented in the centre of the circle. (b)

The subclonal architecture of DIPG101 is evident from a density distribution of subclonal fraction for

each variant in the sample. Although certain mutations such as the H3F3A K27M are present in 100%

of cells, there are numerous variants only present in varying proportions of the tumour mass. (c) Circos

plots from whole exome sequencing of two topographically distinct regions of the DIPG sample 9192,

collected at autopsy, shown with H&E staining. (d) Density map of variant allele frequency plots for all

variants (coding and non-coding) of the distinct regions of DIPG9192 highlighting selected somatic

coding mutations present in both components (along diagonal, e.g. ACVR1) and those present in only

one region or the other (along axes, e.g PIK3CA).


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