Only the genomic features (gene mutations) of a patient’s tumour are analysed at the time of diagnosis due to the limited availability of biopsy material. Although this may identify some genetic characteristics driving tumour growth, few of these mutations are targetable, with even less providing a survival benefit to patients. As DMG tumours are known to be highly heterogeneous (driver mutations vary greatly between and within patient tumours), I-DIMENSIONS seeks to understand the multiple layers influencing DMG across a large selection of tumours so that better-informed treatment strategies can be developed.

I-DIMENSIONS aims to provide medical and research scientists with new data that unlocks effective treatment strategies for DMG. By looking at tumours as a sum of their biological systems (rather than via a single-featured lens), we hope that the developed subtyping system will inform the creation of a therapy selection tool used by clinicians to extend the survival of children diagnosed with brain cancer in the future.

 I-DIMENSIONS is an Integrated Dmg/hgg genomIc Methylomic EpigeNetic Spatial transcrIptomic prOteomic subtypiNg System integrating tumour genomics data (whole genome sequencing–WGS), DNA methylation data (EPIC array) and chromatin landscapes (ATAC-seq) to group patients into methylo-epi-genomic subtypes at diagnosis. Evaluating the spatial heterogeneity (scRNAseq) and the abundance and activity of all proteins (phospho- and proteomic profiling) present in each specimen will provide the most comprehensive picture of the elements sustaining tumour growth, revealing targets to be addressed using precision medicines. Our approach will be informed by utilising 210 samples collected from collaborators worldwide (including about 17 patient samples from the Charlie Teo Foundation Brain Tumour Bank) and be developed by a multi-disciplinary team of international experts.

Critically, I-DIMENSIONS will identify the highly significant influences on the regulation of a tumour’s posttranslational architecture i.e. the non-genomic elements relating to the geographical location of the tumour. The role that endogenous and exogenous microenvironmental influences (such as neurological cues, catecholamines, insulin, growth factors, growth hormones and immune related interactions - scRNAseq), as well as treatment-related neuronal effects from radiotherapy, and corticosteroid use will dictate posttranscriptional and posttranslational effects, that cannot be replicated in in vitro laboratory models.

Hypothesis:

The development of a methylo-epi-genomic subtyping system predictive of the proteomic/phosphoproteomic components of each sample will enable the future stratification of patients into subtypes that are indicative of treatment response.

Aim 1: Develop a novel methylo-epi-genomic subtyping system for DMG.

Aim 2: Identify the key proteomic/phosphoproteomic signatures (drug targets) of each specimen used in the DMG methylo-epi-genomic subtyping system.

Aim 3: Identify the spatial heterogeneity of the disease and relate this back to the proteomic/phosphoproteomic signatures.