Inherited genome instability

Extracranial solid tumors, such as neuroblastoma, Ewing sarcoma, and osteosarcoma, are a leading cause of morbidity and mortality in children. In contrast to adult cancers, in which exogenous mutagens or age-accumulated DNA damage can drive tumor development (1), childhood cancers lack the extended time frame needed to amass the mutations required for tumorigenesis by those routes. Therefore, endogenous mutagenic processes are a likely source for cancer-enabling mutations in pediatric cancers. Yet the detailed biological processes leading to tumorigenesis in these cancers remain mostly unknown. On page 39 of this issue, Gillani et al. (2) report that rare germline structural variants (SVs), which are a family of large DNA rearrangements that vary in size from 50 to millions of nucleotides, are a risk factor for pediatric extracranial solid tumors. The findings suggest that germline SVs may contribute to early genome instability in these cancers and could inform the design of targeted therapies.