Cancer is the leading disease-related cause of death in children in developed countries. Arising in the context of actively growing tissues, childhood cancers are fundamentally diseases of dysregulated development. Childhood cancers exhibit a lower overall mutational burden than adult cancers, and recent sequencing studies have revealed that the genomic events central to childhood oncogenesis include mutations resulting in broad epigenetic changes or translocations that result in fusion oncoproteins. Here, we will review the developmental origins of childhood cancers, epigenetic dysregulation in tissue stem/precursor cells in numerous examples of childhood cancer oncogenesis and emerging therapeutic opportunities aimed at both cell-intrinsic and microenvironmental targets together with new insights into the mechanisms underlying long-term sequelae of childhood cancer therapy.
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The authors extend special thanks to S. Knemeyer for illustrations, to A. Groves for help with Supplementary Table 1 and to K. E. Warren for helpful input on Box 2, Challenges in clinical trials in childhood cancer. The authors acknowledge funding from the Career Award for Medical Scientist from Burroughs Wellcome Fund (M.G.F.), Solving Kids’ Cancer (M.G.F.), The Cure Starts Now Foundation and DIPG Collaborative (M.G.F. and M.M.), National Institutes of Neurological Disorders and Stroke (R01NS092597 to M.M.), National Institutes of Health (DP1NS111132 to M.M.), Abbie’s Army (M.M.), McKenna Claire Foundation (M.M.), Unravel Pediatric Cancer Foundation (M.M.), Alex’s Lemonade Stand Foundation (M.G.F. and M.M.), Maternal and Child Health Research Institute at Stanford (M.M.) and the Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases (M.M.).
The authors declare no competing interests.
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Filbin, M., Monje, M. Developmental origins and emerging therapeutic opportunities for childhood cancer. Nat Med 25, 367–376 (2019). https://doi.org/10.1038/s41591-019-0383-9
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