1. The effect of age on the acquisition and selection of cancer driver mutations in sun-exposed normal skin.
- Author
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Hernando, B., Dietzen, M., Parra, G., Gil-Barrachina, M., Pitarch, G., Mahiques, L., Valcuende-Cavero, F., McGranahan, N., and Martinez-Cadenas, C.
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RISK factors of skin cancer , *GENETIC mutation , *PHYSIOLOGICAL effects of solar radiation , *SKIN biopsy , *PHYSIOLOGICAL effects of ultraviolet radiation , *SQUAMOUS cell carcinoma ,AGE factors in cancer - Abstract
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. 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. 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. 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. • As skin cancer incidence increases, UV-related somatic mutations accumulate exponentially with increasing age in normal epidermis. • UV-related mutations do not only accumulate with age, but also repair processes are less efficient in elderly individuals. • Apart from age, an individual's skin phototype is key in the build-up of somatic mutations in healthy skin. • Distinct mutational processes may operate in different age groups. • Ageing is associated with positive selection and expansion of clones with cancer mutations in sun-exposed normal skin. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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