Uncovering the human foetal origin of childhood cancer (360G-Wellcome-223135_Z_21_Z)

BACKGROUND Despite impressive progress over seven decades, the prognosis of many childhood cancers has now stalled. Novel treatments are required, which may be derived by studying the foetal origin of childhood cancer. My goal is to provide an exact phylogenetic and quantitative molecular understanding of the roots of childhood cancer that may be clinically exploited, for example, by revealing foetal specific antigens, mechanisms of subverted differentiation, or markers for screening. HYPOTHESIS & QUESTIONS My overarching hypothesis is that childhood cancer formation represents a perturbation of human development that extends beyond individual cells, which I will address through two questions: (i) Do childhood cancers arise from pre- cancerous clonal expansions? (ii) Do embryonic cancer-disposed lineages contribute to non-transformed tissues? APPROACH I will reconstruct from resection and post-mortem tissues the embryonic phylogeny of tumours from somatic DNA mutations and interrogate the molecular differences between normal, pre-cancerous, and cancerous tissues through mRNA and methylation sequencing at the resolution of individual histological units. ANTICIPATED OUTCOMES This work will reveal embryonic precursors of specific tumour types and molecular features of malignant transformation. Moreover, it will provide a blueprint for studying the origin of the entire spectrum of childhood cancers and other genetic developmental diseases.