title: Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin.
abstract: How somatic mutations accumulate in normal cells is central to understanding cancer development but is poorly understood. We performed ultradeep sequencing of 74 cancer genes in small (0.8 to 4.7 square millimeters) biopsies of normal skin. Across 234 biopsies of sun-exposed eyelid epidermis from four individuals, the burden of somatic mutations averaged two to six mutations per megabase per cell, similar to that seen in many cancers, and exhibited characteristic signatures of exposure to ultraviolet light. Remarkably, multiple cancer genes are under strong positive selection even in physiologically normal skin, including most of the key drivers of cutaneous squamous cell carcinomas. Positively selected mutations were found in 18 to 32% of normal skin cells at a density of ~140 driver mutations per square centimeter. We observed variability in the driver landscape among individuals and variability in the sizes of clonal expansions across genes. Thus, aged sun-exposed skin is a patchwork of thousands of evolving clones with over a quarter of cells carrying cancer-causing mutations while maintaining the physiological functions of epidermis.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Martincorena
authors.affiliation: MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Amit
authors.initials: A
authors.lastname: Roshan
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK.
authors.forename: Moritz
authors.initials: M
authors.lastname: Gerstung
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Ellis
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK. Francis Crick Institute, London, UK. Department of Human Genetics, University of Leuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Van Loo
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: McLaren
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Wedge
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Fullam
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK.
authors.forename: Ludmil B
authors.initials: LB
authors.lastname: Alexandrov
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Tubio
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Stebbings
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Menzies
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Widaa
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.affiliation: MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, UK. phj20@mrc-cu.cam.ac.uk pc8@sanger.ac.uk.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Jones
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK. Department of Haematology, University of Cambridge, Cambridge, UK. phj20@mrc-cu.cam.ac.uk pc8@sanger.ac.uk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D060965:Clonal Evolution; D004817:Epidermis / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D005143:Eyelids / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D052138:Genes, Neoplasm; D006801:Humans; D009154:Mutation / Q000235:genetics / Q000528:radiation effects; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000473:pathology; D012641:Selection, Genetic; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D047368:Tumor Burden / Q000235:genetics* / Q000528:radiation effects; D014466:Ultraviolet Rays