Toward a Unified Theory of Why Young People Develop Cancer

Epidemiologic and genetic studies have now defined specific patterns of incidence and distinct molecular features of cancers in young versus aging people. Here, I review a general framework for the causes of cancer in children and young adults by relating somatic genetic mosaicism and developmental tissue mutagenesis. This framework suggests how aging-associated cancers such as carcinomas, glioblastomas, and myelodysplastic leukemias are causally distinct from cancers that predominantly affect children and young adults, including lymphoblastic and myeloid leukemias, sarcomas, neuroblastomas, medulloblastomas, and other developmental cancers. I discuss the oncogenic activities of known developmental mutators RAG1/2, AID, and PGBD5, and describe strategies needed to define missing developmental causes of young-onset cancers. Thus, a precise understanding of the mechanisms of tissue-specific somatic mosaicism, developmental mutators, and their control by human genetic variation and environmental exposures is needed for improved strategies for cancer screening, prevention, and treatment.