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The effect of age on the acquisition and selection of cancer driver mutations in sun-exposed normal skin

Hernando, B; Dietzen, M; Parra, G; Gil-Barrachina, M; Pitarch, G; Mahiques, L; Valcuende-Cavero, F; ... Martinez-Cadenas, C; + view all (2021) The effect of age on the acquisition and selection of cancer driver mutations in sun-exposed normal skin. Annals of Oncology , 32 (3) pp. 412-421. 10.1016/j.annonc.2020.11.023. Green open access

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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 127 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 (cSCC) cancer genes and clonally expanded with age, with distinct mutational processes underpinning different age groups. Our results suggest loss of fidelity in transcription-coupled repair later in life. CONCLUSION: Our findings reveal that aging 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.

Type: Article
Title: The effect of age on the acquisition and selection of cancer driver mutations in sun-exposed normal skin
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.annonc.2020.11.023
Publisher version: https://doi.org/10.1016/j.annonc.2020.11.023
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Aging, Next-generation sequencing, Skin Phototype, Somatic mutation, UV exposure, carcinogenesis, mutational spectrum, normal epidermis
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10118323
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