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

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.

Informations de copyright

Copyright © 2020. Published by Elsevier Ltd.

Déclaration de conflit d'intérêts

Disclosure NM has received consultancy fees and has stock options in Achilles Therapeutics. All remaining authors have declared no conflicts of interest. Data sharing Sequencing data have been deposited at the European Genome–phenome Archive (EGA) under the accession code EGAS00001004279. The somatic mutations found in all samples are listed in the Supplementary Dataset S1, available at https://doi.org/10.1016/j.annonc.2020.11.023. Clinical data of each donor can be found in the Supplementary Dataset S2, available at https://doi.org/10.1016/j.annonc.2020.11.023. Any other relevant data can be obtained from the corresponding authors upon reasonable request.