title: Ontogenic growth as the root of fundamental differences between childhood and adult cancer.
abstract: Cancer, the unregulated proliferation of cells, can occur at any age and may arise from almost all cell types. However, the incidence and types of cancer differ with age. Some cancers are predominantly observed in children, others are mostly restricted to older ages. Treatment strategies of some cancers are very successful and cure is common in childhood, while treatment of the same cancer type is much more challenging in adults. Here, we develop a stochastic model of stem cell proliferation that considers both tissue development and homeostasis and discuss the disturbance of such a system by mutations. Due to changes in population size, mutant fitness becomes context dependent and consequently the effects of mutations on the stem cell population can vary with age. We discuss different mutant phenotypes and show the age dependency of their expected abundances. Most importantly, fitness of particular mutations can change with age and advantageous mutations can become deleterious or vice versa. This perspective can explain unique properties of childhood disorders, for example, the frequently observed phenomenon of a self-limiting leukemia in newborns with trisomy 21, but also explains other puzzling observations such as the increased risk of leukemia in patients with bone marrow failure or chemotherapy induced myelodysplasia.
authors.affiliation: Department of Evolutionary Theory, Max Planck Institute for Evolutionary Biology, Plön, Germany.|Centre for Evolution and Cancer, The Institute of Cancer Research, Sutton, London, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Werner
authors.affiliation: Department of Evolutionary Theory, Max Planck Institute for Evolutionary Biology, Plön, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Traulsen
authors.affiliation: Division of Haematology and Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.|Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: David
authors.initials: D
authors.lastname: Dingli
mesh_terms: D000328:Adult; D000367:Age Factors; D049109:Cell Proliferation / Q000235:genetics*; D002675:Child, Preschool; D004314:Down Syndrome / Q000150:complications / Q000235:genetics*; D006801:Humans; D007938:Leukemia / Q000150:complications / Q000235:genetics*; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000473:pathology*
keywords: Acute lymphocytic leukemia; Acute myelogenous leukemia; Adult haematopoietic stem cells; Cancer stem cells; Hemopoietic stem cells; Self-renewal