Normal skin contains numerous clones carrying cancer driver mutations. However, the
mutational landscape of normal skin and its clonal relationship with skin cancer requires
further elucidation. The aim of our study was to investigate the mutational landscape
of normal human skin. We performed whole-exome sequencing using physiologically normal
skin tissues and the matched peripheral blood (n = 39) and adjacent-matched skin cancers
from a subset of patients (n = 10). Exposed skin harbored a median of 530 mutations
(10.4/mb, range = 51–2,947), whereas nonexposed skin majorly exhibited significantly
fewer mutations (median = 13, 0.25/mb, range = 1–166). Patient age was significantly
correlated with the mutational burden. Mutations in six driver genes (NOTCH1, FAT1, TP53, PPM1D, KMT2D, and ASXL1) were identified. De novo mutational signature analysis identified a single signature
with components of UV- and aging-related signatures. Normal skin harbored only three
instances of copy-neutral loss of heterozygosity in 9q (n = 2) and 6q (n = 1). The
mutational burden of normal skin was not correlated with that of matched skin cancers,
and no protein-coding mutations were shared. In conclusion, we revealed the mutational
landscape of normal skin, highlighting the role of driver genes in the malignant progression
of normal skin.
Abbreviations:
BCC (basal cell carcinoma), CNA (copy number alteration), CN-LOH (copy-neutral loss of heterozygosity), cSCC (cutaneous squamous cell carcinoma), KC (keratinocyte), WES (whole-exome sequencing)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: January 27, 2023
Accepted:
January 7,
2023
Received in revised form:
December 15,
2022
Received:
September 24,
2022
accepted manuscript published online XXX; corrected proof published online XXXPublication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.
