The Relative Contributions of Germline Variation, Epimutation, and Somatic Mutation to Paediatric Leukaemia Predisposition

The next-generation sequencing era has repeatedly demonstrated that the amount of acquired somatic mutations in paediatric cancers can rarely account for the total incidence of any cancer subtype. In addition, many cancer-related mutations can be found in healthy individuals. These findings strongly suggest that additional genetic or epigenetic variation is required for malignant transformation, particularly in children who have significantly less environmental exposure and resulting genetic damage. Current studies now suggest that 3–33% of paediatric cancer patients have a predisposition to cancer. These germline genetic or epigenetic changes are frequently found in molecular mechanisms regulating normal human development which have long informed our understanding of developmental biology. Blockade of development is a mechanism of transformation consistent with the higher number of immature cancer cell types in paediatric patients. Thus, while nearly every cancer is a combination of germline variation and somatic mutation, the relative contribution to tumourigenesis in paediatrics is weighted toward germline changes. This review will explore how paediatric predisposition to leukaemia is influenced by germline genetic and epigenetic variability of variable penetrance. Improved understanding of these critical developmental mechanisms will lead to improved surveillance and perhaps guide a new class of therapeutics aimed at promoting normal differentiation rather than widespread cytotoxicity.