B Hernando1, M Dietzen2, G Parra3, M Gil-Barrachina1, G Pitarch4, L Mahiques4, F Valcuende-Cavero5, N McGranahan6, C Martinez-Cadenas7. 1. Department of Medicine, Jaume I University of Castellon, Castellon, Spain. 2. Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, UK. 3. Centre Nacional d'Anàlisi Genòmica-Centre de Regulació Genòmica (CNAG-CRG), Barcelona, Spain. 4. Department of Dermatology, Castellon University General Hospital, Castellon, Spain. 5. Department of Dermatology, La Plana University Hospital, Villarreal, Spain. 6. Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, UK. Electronic address: nicholas.mcgranahan.10@ucl.ac.uk. 7. Department of Medicine, Jaume I University of Castellon, Castellon, Spain. Electronic address: ccadenas@uji.es.
Abstract
BACKGROUND: The accumulation of somatic mutations contributes to ageing and cancer. Sunlight is the principal aetiological factor associated with skin cancer development. However, genetic and phenotypic factors also contribute to skin cancer risk. This study aimed at exploring the role of photoaging, as well as other well-known epidemiological risk factors, in the accumulation of somatic mutations in cancer-free human epidermis. MATERIAL AND METHODS: We deeply sequenced 46 genes in normal skin biopsies from 123 healthy donors, from which phenotypic data (including age, pigmentation-related genotype and phenotype) and sun exposure habits were collected. We determined the somatic mutational burden, mutational signatures, clonal selection and frequency of driver mutations in all samples. RESULTS: Our results reveal an exponential accumulation of UV-related somatic mutations with age, matching skin cancer incidence. The increase of mutational burden is in turn modified by an individual's skin phototype. Somatic mutations preferentially accumulated in cutaneous squamous cell carcinoma cancer genes and clonally expanded with age, with distinct mutational processes underpinning different age groups. Our results suggest a loss of fidelity in transcription-coupled repair later in life. CONCLUSION: Our findings reveal that ageing is not only associated with an exponential increase in the number of somatic mutations accumulated in normal epidermis, but also with selection and expansion of cancer-associated mutations. Aged, sun-exposed normal skin is thus an extended mosaic of multiple clones with driver mutations, poised for the acquisition of transforming events.
BACKGROUND: The accumulation of somatic mutations contributes to ageing and cancer. Sunlight is the principal aetiological factor associated with skin cancer development. However, genetic and phenotypic factors also contribute to skin cancer risk. This study aimed at exploring the role of photoaging, as well as other well-known epidemiological risk factors, in the accumulation of somatic mutations in cancer-free human epidermis. MATERIAL AND METHODS: We deeply sequenced 46 genes in normal skin biopsies from 123 healthy donors, from which phenotypic data (including age, pigmentation-related genotype and phenotype) and sun exposure habits were collected. We determined the somatic mutational burden, mutational signatures, clonal selection and frequency of driver mutations in all samples. RESULTS: Our results reveal an exponential accumulation of UV-related somatic mutations with age, matching skin cancer incidence. The increase of mutational burden is in turn modified by an individual's skin phototype. Somatic mutations preferentially accumulated in cutaneous squamous cell carcinoma cancer genes and clonally expanded with age, with distinct mutational processes underpinning different age groups. Our results suggest a loss of fidelity in transcription-coupled repair later in life. CONCLUSION: Our findings reveal that ageing is not only associated with an exponential increase in the number of somatic mutations accumulated in normal epidermis, but also with selection and expansion of cancer-associated mutations. Aged, sun-exposed normal skin is thus an extended mosaic of multiple clones with driver mutations, poised for the acquisition of transforming events.
Authors: Katarzyna Klonowska; Joannes M Grevelink; Krinio Giannikou; Barbara A Ogorek; Zachary T Herbert; Aaron R Thorner; Thomas N Darling; Joel Moss; David J Kwiatkowski Journal: J Clin Invest Date: 2022-05-16 Impact factor: 19.456
Authors: Hanxin Lin; Raymond H Kim; Nika Maani; Karen Panabaker; Jeanna M McCuaig; Kathleen Buckley; Kara Semotiuk; Kirsten M Farncombe; Peter Ainsworth; Seema Panchal; Bekim Sadikovic; Susan Randall Armel Journal: NPJ Genom Med Date: 2021-07-19 Impact factor: 8.617