On the origins of pediatric brain cancer:Exploring the role of genome instability in development and disease

Childhood brain cancerEvery year, more than 100 children are diagnosed with brain cancer in the Netherlands. Although most are cured, survivors face severe neurological problems later in life. This calls for better strategies to tackle the disease, from a better understanding of its origin to the development of treatments that target the tumor cell more specifically.Brain developmentEarly in human development, the basic brain structure of the future fetus starts to develop – lasting up to 2 years after birth. During this long period of time, brain cells divide intensively to form the entire brain structure. The division of brain cells is dependent on signaling pathways. Any deviation in those signaling pathways will hinder normal brain development. Very often, errors in these growth pathways are found in childhood brain cancer. Therefore, brain cancers in children can be defined as a developmental disease, in which normal development takes a wrong turn.Genome instabilityIn order to build a functional (brain) tissue, cells undergo an amplification process called cell division. Cell division means that the entire repertoire of genes -the genome- is passed on to two daughter cells. During each division, cells face threats that if not countered, damage the genome and lead to genome instability. Genome instability is believed to be present during normal brain development due to the high division rate of the brain cells.The work described in this thesis investigates the role of genome instability in the development of brain cancer in children. Our research paves the way for the discovery of new therapeutic targets that could be used in the future to better treat this deadly disease