Following the footprints: Mutational patterns in tumors of children with mismatch repair deficiency syndromes

DNA is vital, but it is damaged every day by influences in- and outside the body. This damage, better known as mutations, is repaired by mechanisms such as Mismatch Repair (MMR). The genes MLH1, MSH2, MSH6, and PMS2 are essential for MMR. A defect in one of the copies of one of these genes causes Lynch syndrome (LS). This results in an increased risk of cancer in adulthood. In LS tumors, the second copy of the MMR gene is often also defective, causing MMR to malfunction and mutations to accumulate. If there is a defect in both copies of an MMR gene in all cells, this leads to constitutional mismatch repair deficiency syndrome (CMMRD). This causes a high risk of developing multiple tumors at a young age. People with LS or CMMRD get regular surveillance so tumors can be detected early and treated as effectively as possible. For LS, surveillance starts in adulthood, but LS is being diagnosed increasingly in children with cancer. In this thesis, we use mutational patterns to determine whether there is a link between LS and childhood cancer, and whether surveillance should be started earlier. For CMMRD, surveillance does start at a young age, but not all tumors are detected early. Furthermore, treating these tumors is challenging; multiple medications cannot be used because they are ineffective or pose too high a risk. New methods for treating and preventing tumors are therefore very important. In this thesis, we use mutational patterns to better understand the mutational processes in CMMRD tumors and adapt treatments accordingly.