High burden and pervasive positive selection of somatic mutations in normal human skin
Open accessAbstract
Normal skin's curiously abnormal genome: Within every tumor, a battle is being waged. As individual tumor cells acquire new mutations that promote their survival and growth, they clonally expand at the expense of tumor cells that are “less fit.” Martincorena et al. sequenced 234 biopsies of sun-exposed but physiologically normal skin from four individuals (see the Perspective by Brash). They found a surprisingly high burden of mutations, higher than that of many tumors. Many of the mutations known to drive the growth of cutaneous squamous cell carcinomas were already under strong positive selection. More than a quarter of normal skin cells carried a driver mutation, and every square centimeter of skin contained hundreds of competing mutant clones. Science , this issue p. 880 ; see also p. 867
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The shallow increase in UV-specific mutations in normal cells is consistent with efficient repair minimizing UV-induced mutations and skin cancer initiation in repair-proficient cells.
“Additionally, normal cells showed a smaller, shallow increase in UV-specific mutations with UVC dose, as is consistent with efficient repair that minimizes UV-induced mutations and skin cancer initiation in repair-proficient cells (10).”
From Why Cockayne syndrome patients do not get cancer despite their DNA repair deficiency (2016) · cites this paper as [10]
The “Mutational signature of ultraviolet light exposure in normal skin” section (page unavailable) reports UV-associated mutations and a strand bias consistent with transcription-coupled repair. It does not examine UVC dose responses or show that efficient repair minimizes UV-induced mutations or skin cancer initiation in repair-proficient cells. (LLM, conf=0.83)
Experimental — accuracy not yet measuredCancer, especially in skin, is associated with mutagenesis.
“Because cancer, especially in skin, is associated with mutagenesis (9, 10), we hypothesized that, unlike defects in GGR, which are associated with enhanced UV-induced mutagenesis in XP-C cells (11), the”
From Why Cockayne syndrome patients do not get cancer despite their DNA repair deficiency (2016) · cites this paper as [10]
Previous studies point to pol η being an important mutagenic factor in normal skin and cancer cells.
“Thus, all these studies point to pol h being an important mutagenic factor in normal skin and cancer cells.”
From DNA polymerase <b>η</b> mutational signatures are found in a variety of different types of cancer (2018) · cites this paper as [20]
Activating oncogenic mutations alone do not allow the immune system to eliminate the affected cell, since such mutations occur frequently in normal tissues.
“Mutational activation of a single or multiple oncogenes is, however, insufficient for immune eradication of an oncogene-activated cell, reflected by the existence of oncogenic mutations at a high rate within normal tissues160.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [160]
Clonal expansion has also been found in other human tissues, including skin, colon and oesophagus, and is thought to be a normal, possibly ubiquitous, process associated with ageing in all tissues, in particular those that experience significant cellular turnover.
“Clonal expansion has also been found in other human tissues, including skin, colon and oesophagus52–54, and is thought to be a normal, possibly ubiquitous, process that is associated with ageing in all tissues, in particular those that experience significant cellular turnover.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [54]
An equivalent state of somatic mutation-driven clonal expansions is pervasive in the epithelium of skin and esophagus, suggesting such expansions may be a characteristic of aging in several tissues.
“An equivalent state is also pervasive in the epithelium of skin 14 and esophagus 15,16, suggesting that somatic mutation-driven clonal expansions may be a characteristic of aging in several tissues.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [14]
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- Authors
- Martincorena, I., Roshan, A., Gerstung, M., Ellis, P., Van Loo, P., McLaren, S., Wedge, D. C., Fullam, A., Alexandrov, L. B., Tubio, J. M., Stebbings, L., Menzies, A., Widaa, S., Stratton, M. R., Jones, P. H., & Campbell, P. J.
- Affiliations
- Wellcome Sanger Institute (GB)
- University of Cambridge (GB)
- Wellcome Trust Sanger Institute, Hinxton CB10 1SA, Cambridgeshire, UK.
- Corresponding author
- Jones, Philip H.
- Campbell, Peter J.
- ORCID
- Venue
- Science
- Published
- 2015-05-22
- Volume
- 348
- Issue
- 6237
- Pages
- 880-886
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4471149
- OpenAlex
- W1956871134
- Cited by
- 1,770
- References
- 52
- Citations by year
- 2026: 105 · 2025: 141 · 2024: 152 · 2023: 159 · 2022: 184 · 2021: 199 · 2020: 200 · 2019: 180 · 2018: 139 · 2017: 149 · 2016: 122 · 2015: 34 · 2014: 3
- FWCI
- 48.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Figshare (submittedVersion, cc-by)
- Lirias (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- EMBO (1287-2012)
- Wellcome Trust (077012/Z/05/Z)
- Medical Research Council
- MRC
- Cancer Research UK (C609/A17257)
- Wellcome Trust Senior Clinical Research Fellowship (WT088340MA)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Epidemiology › Nonmelanoma Skin Cancer Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- somatic mutations, normal skin, positive selection, cancer driver genes, UV exposure, cutaneous squamous cell carcinoma, clonal expansion, mutational burden, skin aging
- MeSH terms
- Carcinoma, Squamous Cell, Epidermis, Eyelids, Humans, Mutation, Neoplasms, Radiation-Induced, Selection, Genetic, Skin Neoplasms, Ultraviolet Rays, Tumor Burden, Genes, Neoplasm, Clonal Evolution
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