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Relating evolutionary selection and mutant clonal dynamics in normal epithelia.
Hall, Michael W J; Jones, Philip H; Hall, Benjamin A.
Afiliación
  • Hall MWJ; Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
  • Jones PH; MRC Cancer Unit, University of Cambridge, Hutchison-MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
  • Hall BA; Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
J R Soc Interface ; 16(156): 20190230, 2019 07 26.
Article en En | MEDLINE | ID: mdl-31362624
ABSTRACT
Cancer develops from mutated cells in normal tissues. Whether somatic mutations alter normal cell dynamics is key to understanding cancer risk and guiding interventions to reduce it. An analysis of the first incomplete moment of size distributions of clones carrying cancer-associated mutations in normal human eyelid skin gives a good fit with neutral drift, arguing mutations do not affect cell fate. However, this suggestion conflicts with genetic evidence in the same dataset that argues for strong positive selection of a subset of mutations. This implies cells carrying these mutations have a competitive advantage over normal cells, leading to large clonal expansions within the tissue. In the normal epithelium, clone growth is constrained by the limited size of the proliferating compartment and competition with surrounding cells. We show that if these factors are taken into account, the first incomplete moment of the clone size distribution is unable to exclude non-neutral behaviour. Furthermore, experimental factors can make a non-neutral clone size distribution appear neutral. We validate these principles with a new experimental dataset showing that when experiments are appropriately designed, the first incomplete moment can be a useful indicator of non-neutral competition. Finally, we discuss the complex relationship between mutant clone sizes and genetic selection.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Selección Genética / Células Epiteliales / Modelos Genéticos / Mutación Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J R Soc Interface Año: 2019 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: ENGLAND / ESCOCIA / GB / GREAT BRITAIN / INGLATERRA / REINO UNIDO / SCOTLAND / UK / UNITED KINGDOM

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Selección Genética / Células Epiteliales / Modelos Genéticos / Mutación Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J R Soc Interface Año: 2019 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: ENGLAND / ESCOCIA / GB / GREAT BRITAIN / INGLATERRA / REINO UNIDO / SCOTLAND / UK / UNITED KINGDOM