Tracing the origin of childhood cancer through somatic mutations

Cancer is the disease that kills the most children in developed countries, and novel therapies are urgently needed. The answer could be to target the cancer cell of origin.

My host supervisor has developed a method to trace the cell of origin through DNA sequencing (WGS) using the fact that every cell has a unique combination of mutations.

I will therefore 1) define the cell of origin (precursor) in the liver tumour hepatoblastoma, 2) identify how the tumour arises and 3) determine the molecular differences between cancer, precursor and normal cells.I will be the lead researcher and work fulltime on this project. WGS will be performed on paediatric hepatoblastoma tumour and paired normal liver tissue (year 1).

Mutations will be identified and used to trace the tumour history, define the cell of origin and how the tumour arises (year 1-2).

We will cut out defined regions of cancer, precursor and normal cells with laser microdissection and determine how they differ with multi-omic (DNA, RNA and methylation) analysis (year 2-3). Through state of the art sequencing, I will determine how heaptoblastoma arises and its cell of origin. This may build a novel conceptual framework for childhood tumour formation with broad applicability.

Knowing the tumour origin allows for 1) screening healthy children for risk of developing hepatoblastoma, 2) predicting patient outcome and guiding therapy and 3) improved treatments specifically targeting the cell of origin, while sparing normal cells.