A deep dive into childhood cancer predisposition: Insights from an individual patient perspective

Each year, around 600 children in the Netherlands are diagnosed with cancer, and about 10% have a cancer predisposition syndrome (CPS)—a hereditary condition caused by a germline pathogenic variant that increases the risk to develop cancer. Early recognition of a CPS is crucial for optimizing treatment, enabling family screening, and implementing tumor surveillance. However, in some children strongly suspected of having a CPS, no known genetic cause is found, indicating incomplete knowledge of childhood cancer predisposition.
This thesis aimed to expand understanding of CPSs through identification of novel childhood cancer predisposition genes and improved insights into known ones. Detailed germline and tumor analyses were performed in both individual patients and small cohorts. In single-patient studies, novel or potential predisposition genes were described, including a germline PAX5 deletion in a child with leukemia, a FBXO11 deletion in a child with lymphoma, and an RRAS variant in a child with myelodysplastic syndrome.
Cohort studies provided new insights into SMARCA4, supporting a possible role in neuroblastoma. In addition, using novel sequencing techniques we explored the genetic basis of the very rare ROHHAD(-NET) syndrome, though no causative variants were identified. Germline structural variant analysis using optical genome mapping also proved highly accurate, though no causative variants were identified.
Overall, these findings highlight the importance of integrating clinical and genomic data, advanced sequencing techniques, and international collaboration to uncover unknown genetic causes of CPSs. Continuing investigation of unsolved cases remains crucial to better understand cancer predisposition in children and to discover novel childhood cancer predisposition genes.