Publication Date:
2015-05-23
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471149/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471149/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Martincorena, Inigo -- Roshan, Amit -- Gerstung, Moritz -- Ellis, Peter -- Van Loo, Peter -- McLaren, Stuart -- Wedge, David C -- Fullam, Anthony -- Alexandrov, Ludmil B -- Tubio, Jose M -- Stebbings, Lucy -- Menzies, Andrew -- Widaa, Sara -- Stratton, Michael R -- Jones, Philip H -- Campbell, Peter J -- 077012/Z/05/Z/Wellcome Trust/United Kingdom -- 093867/Wellcome Trust/United Kingdom -- 103858/Wellcome Trust/United Kingdom -- C609/A17257/Cancer Research UK/United Kingdom -- WT088340MA/Wellcome Trust/United Kingdom -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 May 22;348(6237):880-6. doi: 10.1126/science.aaa6806.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK. ; MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, UK. ; Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK. Francis Crick Institute, London, UK. Department of Human Genetics, University of Leuven, Leuven, Belgium. ; MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, UK. phj20@mrc-cu.cam.ac.uk pc8@sanger.ac.uk. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25999502" target="_blank"〉PubMed〈/a〉
Keywords:
Carcinoma, Squamous Cell/*genetics/pathology
;
*Clonal Evolution
;
Epidermis/metabolism/pathology/radiation effects
;
Eyelids/metabolism/pathology/radiation effects
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*Genes, Neoplasm
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Humans
;
*Mutation/genetics/radiation effects
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Neoplasms, Radiation-Induced/genetics/pathology
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*Selection, Genetic
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Skin Neoplasms/*genetics/pathology
;
Tumor Burden/*genetics/radiation effects
;
Ultraviolet Rays
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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