A recent collaboration between the Wellcome Sanger Institute and the Skin Research Institute of Singapore (SRIS) has been published in Nature Genetics. The study revealed that the incidence of certain types of skin cancer in the UK population is up to 17 times higher than that of Singapore, despite receiving 2-3 times less ultraviolet (UV) radiation.
Skin cancer’s building blocks
Keratinocyte carcinoma is a malignant neoplasm formed of keratinocytes – the building blocks of the epidermis. This type of skin cancer can result from abnormal proliferations of either basal or squamous cell keratinocytes and is primarily associated with cumulative UV exposure over an individual’s lifetime. The impacts of exposure can vary due to environmental factors including age, working outdoors or using tanning beds, as well as biological factors such as low skin pigmentation levels.
A higher cumulative UV exposure is associated with a greater risk of developing keratinocyte carcinoma. However, recent research revealed that the UK population has a 17-times higher incidence of keratinocyte carcinoma than the population of Singapore. The average daily maximum UV index in the UK is 3, whereas in Singapore it is 8.
The team at the Wellcome Sanger Institute reasoned that there must be genetic factors underpinning this result, hypothesising that the healthy skin mutational landscape may hold the answer to our questions.
Why UV light isn’t the only factor
The team analysed tissue sample data from five donors from Singapore (mean donor age = 62 years) and six from the UK (mean donor age = 68) and detected a total of 13,850 mutations across the cohort. However, the number of mutations present per donor was four times higher in the UK samples than those from Singapore (Fig. 1).
The type of mutation present between populations was also significant. Of the 10,311 single-base substitutions (SBS) identified across the whole sample, six reference signatures were found: SBS1, SBS5 and SBS7a-d. SBS1 and SBS5 have been previously identified and associated with normal tissue ageing, whereas SBS7a-d result from UV lesions and their subsequent repair. Mutational signature analysis of Singaporean donor data displayed dominance by SBS1 and SBS5, whereas UK donor data were dominated by SBS7a-d. This suggests that mutations in UK skin are primarily associated with UV damage rather than normal ageing processes, unlike in Singaporean skin.
Mutations were also identified in the following genes of interest: NOTCH1, NOTCH2, NOTCH3, TP53 and FAT1. Previous studies have found that these five genes are commonly mutated in incidences of keratinocyte cancer, suggesting that the tumours develop from somatic clones where said genes are mutated. The TP53 gene usually inhibits tumour growth but the mutant TP53 gene is most strongly selected in UK donors. The NOTCH1 and NOTCH2 genes are primarily associated with the regulation of cell differentiation, proliferation and homeostasis. The mutant NOTCH1 and 2 genes are most strongly selected in Singaporean donors (Fig. 1).
These findings indicate that keratinocyte cancers develop in the UK population primarily through the loss of function of TP53, which results from cell-extrinsic processes such as UV damage. In contrast, keratinocyte cancers in the Singapore population appear to develop from errors in cell-intrinsic processes such as DNA replication and repair mechanisms.
Figure 1 | A representation of protein-altering mutations in 1 cm2 of skin from donors from Singapore and the UK. Mutations are displayed as circles, coloured by the gene type. The size of the circle indicates the copy number of clones. The location of subclones can be treated as random. Adapted from King et al., 2023.
It’s in our DNA
These findings suggest that keratinocyte cancers are more common in the United Kingdom because healthy skin from the UK population already shares several characteristics with keratinocyte cancer. These include a high mutational burden, a dominant UV-induced mutation pattern and increased presence of mutated TP53 genes. In contrast, keratinocyte cancers in the Singaporean population appear to develop from errors in cell-intrinsic processes such as genetic replication and repair mechanisms, which are much less common.
Understanding these distinct mechanisms could lead to targeted interventions for skin cancer prevention and treatment based on the underlying genetic factors. Lead author Dr Charlotte King commented on the implications of their research: “These findings help us understand why the UK has such a high incidence of keratinocyte skin cancers. We hope our study encourages others to look at further diverse populations – across the spectrum of cancer risk – for clues on how we can better prevent this common cancer.”