Pervasive Induction of Regulatory Mutation Microclones in Sun-exposed Skin

Area of Science:

• Genomics
• Dermatology
• Cancer Research

Background:

• Carcinogen-induced mutations were previously thought to be random.
• Cancer driver mutations were considered rare and responsible for clonal expansion.

Purpose of the Study:

• To investigate the mutation landscape in human skin after sun exposure.
• To determine the frequency and behavior of UV-induced mutations.

Main Methods:

• Utilized high-fidelity Duplex Sequencing for sensitive mutation detection (down to 4×10^-9 per nt).
• Analyzed mutation frequency and clonal expansion in skin biopsies.
• Conducted in vitro experiments with chronic low-dose UV exposure.

Main Results:

• Sun exposure induces pervasive mutations at UV-sensitive cyclobutane pyrimidine dimer (CPD) hyperhotspots in gene promoters.
• Mutation frequency in sun-exposed skin was significantly higher (8,000-fold increase) than previously reported.
• CPD hyperhotspot mutations exhibited mini-driver clonal expansion, occurring rapidly and frequently.
• In vitro, CPD hyperhotspot mutations arose faster and at higher frequencies than tumor hotspot mutations.

Conclusions:

• UV radiation creates a high burden of mutations in skin, targeting specific hypermutable sites.
• These UV-targeted mutations act as mini-drivers, influencing clonal expansion in skin cells.
• The findings challenge the notion of random mutations, highlighting targeted mutagenesis by UV radiation.