title: Should tissue structure suppress or amplify selection to minimize cancer risk?
abstract: It has been frequently argued that tissues evolved to suppress the accumulation of growth enhancing cancer inducing mutations. A prominent example is the hierarchical structure of tissues with high cell turnover, where a small number of tissue specific stem cells produces a large number of specialized progeny during multiple differentiation steps. Another well known mechanism is the spatial organization of stem cell populations and it is thought that this organization suppresses fitness enhancing mutations. However, in small populations the suppression of advantageous mutations typically also implies an increased accumulation of deleterious mutations. Thus, it becomes an important question whether the suppression of potentially few advantageous mutations outweighs the combined effects of many deleterious mutations.
  
  
  
  We argue that the distribution of mutant fitness effects, e.g. the probability to hit a strong driver compared to many deleterious mutations, is crucial for the optimal organization of a cancer suppressing tissue architecture and should be taken into account in arguments for the evolution of such tissues.
  
  
  
  We show that for systems that are composed of few cells reflecting the typical organization of a stem cell niche, amplification or suppression of selection can arise from subtle changes in the architecture. Moreover, we discuss special tissue structures that can suppress most types of non-neutral mutations simultaneously.
  
  
  
  This article was reviewed by Benjamin Allen, Andreas Deutsch and Ignacio Rodriguez-Brenes. For the full reviews, please go to the Reviewers' comments section.
authors.affiliation: Max Planck Institute for Evolutionary Biology, August-Thienemann-Str. 2, Plön, 24306, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Hindersin
authors.affiliation: The Centre for Evolution and Cancer, The Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Werner
authors.affiliation: Division of Hematology and Department of Molecular Medicine, Mayo Clinic, 200 First Street SW, Rochester, 55905, MN, USA.
authors.forename: David
authors.initials: D
authors.lastname: Dingli
authors.affiliation: Max Planck Institute for Evolutionary Biology, August-Thienemann-Str. 2, Plön, 24306, Germany. traulsen@evolbio.mpg.de.
authors.forename: Arne
authors.initials: A
authors.lastname: Traulsen
mesh_terms: D002454:Cell Differentiation; D006801:Humans; D008962:Models, Theoretical; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000503:physiopathology