The study of childhood cancer and associated syndromes, such as those that result in global or regional overgrowth, has resulted in important insights into basic biological processes and substantial clinical benefits. Through the Factors Associated with Childhood Tumours (FACT) and Childhood Overgrowth Genetics (COG) studies, we recruit and phenotype families with childhood cancer and/or overgrowth and have over 6000 participants. We have already used these unique studies to identify common and rare genetic and epigenetic susceptibility factors for these conditions. However, these only account for a minority of children. The proposed research will extend our research and will address three key questions: 1. What are the genetic and epigenetic factors that predispose to childhood cancer and/or overgrowth conditions? 2. What are the distinctive somatic characteristics of cancers that arise in children with genetic or epigenetic susceptibility conditions? 3. How can we translate these findings for clinical benefit? We will employ genome-wide exomic, genomic and methylation analyses to discover new predisposition factors, together with targeted replication and large-scale characterisation analyses to define prevalence, penetrance, associated clinical features, the spectrum of pathogenic mutations and genotype-phenotype associations. The tumour analyses will yield insights into tumourigenesis and can provide unique information about the timing and order of molecular events i n tumours, as the predisposing mutation is clearly the initiating/first event. We will integrate these data to define the clinically relevant information required for clinical translation of new genes/epigenetic defects and to produce diagnostic, management and testing protocols for use in clinical practice.