The following is a summary of “Mutational Landscape of Normal Human Skin: Clues to Understanding Early-Stage Carcinogenesis in Keratinocyte Neoplasia,” published in the July 2023 issue of Investigative Dermatology by Kim et al.

The normal epidermis contains a large number of clones with cancer-causing mutations. The mutational landscape of normal skin and its clonal relationship with skin cancer must be elucidated in greater detail. Our study aimed to examine the mutational landscape of normal human skin. 

We performed whole-exome sequencing using physiologically normal skin tissues and matched peripheral blood (n = 39) and adjacent-matched skin malignancies from a subset of patients (n = 10). Exposed skin had a median of 530 mutations (10.4/mb, range = 51–2,947), whereas nonexposed skin had substantially fewer mutations (median = 13; 0.25/mb, range =  1–166). The mutational burden was significantly correlated with the age of the patient. Six driver genes (NOTCH1, FAT1, TP53, PPM1D, KMT2D, and ASXL1) contained mutations. Analysis of de novo mutational signatures revealed a singular signature with UV- and aging-related components. 

Only three instances of copy-neutral loss of heterozygosity in 9q (n = 2) and 6q (n = 1) were detected in normal epidermis. There was no correlation between the mutational burden of normal skin and matched skin malignancies, and no protein-coding mutations were shared. In conclusion, we disclosed the mutational landscape of normal skin and highlighted the role of driver genes in malignancy progression in normal skin.

Source: sciencedirect.com/science/article/abs/pii/S0022202X23000246