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

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.

Genomic Progression of Precancerous Actinic Keratosis to Squamous Cell Carcinoma

“…Our study showed that the majority of SCC and SE/SCCIS/AK pairs (69.2%, 9/13) harbored NOTCH1 or TP53 driver mutations in common trunks, suggesting that these mutations played key roles in early skin carcinogenesis. Consistent with our findings, previous studies reported prevalent NOTCH1 and TP53 mutations in AK/SCCISs (Chitsazzadeh et al, 2016, Lazo de la Vega et al, 2020, South et al, 2014 and sun-exposed normal skin (Fowler et al, 2021, Hernando et al, 2021, Martincorena et al, 2015, Wei et al, 2021. However, in a recent study (Zheng et al, 2021), UV-induced mutant clones in the epidermis and SCCIS lesion were found to be complex, suggesting that not all SCC and SE/SCCIS/AK pairs are clonally related.…”

“…Further large-scale studies will be required to explore the oncogenic implications of the NOTCH1 mutations. Interestingly, most of the NOTCH1 (18/22) and TP53 mutations (9/11) identified in this study were detected in normal skin (Fowler et al, 2021, Hernando et al, 2021, Martincorena et al, 2015, Wei et al, 2021, which might support a stepwise progression of NOTCH1or TP53-mutant cells in normal skin to AK/SCCIS and SCC.…”

“…To our knowledge, this is the first report of FBXW7 R465C in cutaneous SCC (2 samples). Some of the mutations have also been reported J o u r n a l P r e -p r o o f in normal skin or AK/SCCIS: TP53 X261_splice (Fowler et al, 2021), CDKN2A R58X (Hernando et al, 2021), and PIK3CA R357Q/A1035V (Fowler et al, 2021, Martincorena et al, 2015, and MYC-amplification (Toll et al, 2009). We also identified that unique mutations in SCCs were heterogeneous from case to case, suggesting several possibilities: diverse genes/pathways can drive the progression to SCC, genetic alteration events restricted to SCC identified in this study are not sufficient to mediate progression from AK, and/or there is a more critical genomic or epigenetic event that is yet to be identified.…”

Incidental findings from cancer next generation sequencing panels

“…Sample mix-up was ruled out by the assessment of three unique SNPs on skin and blood samples and results were confirmed using an additional NGS chemistry and sequencer. Taken together, the two additional variants found in the direct skin biopsy were likely somatic events isolated to the skin which have been observed in healthy individuals [36][37][38] . Conversely, Patient 6 harboured low levels of a TP53 variant in direct skin punch biopsy, suggestive of PBL contamination in the biopsy sample.…”

Cells to Surgery Quiz: January 2022

“…Loss of NOTCH signaling has been shown to increase tumorigenesis in mouse models of head and neck SCC (Nyman et al, 2018). These alterations were also identified in normal skin (Fowler et al, 2021;Hernando et al, 2021;Martincorena et al, 2015;Wei et al, 2021). Kim et al (2021) suggest that this is secondary to UV exposure/photodamage and that perhaps there are subsets of normal skin-KCs with or without the genetic variations (such as NOTCH1 alterations) predisposing them to cancer (Kim et al, 2021).…”