Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin.
Level 4 - case-series / case-control
Descriptive genomic profiling of human tissue biopsies without a clinical comparison group.
PubMed 25999502 · doi:10.1126/science.aaa6806
What was done
Researchers performed ultradeep sequencing of 74 cancer-related genes on 234 micro-biopsies (0.8 to 4.7 mm²) of physiologically normal, sun-exposed eyelid epidermis collected from four human donors to analyze somatic mutation accumulation and clonal architecture.
What was found
Normal eyelid skin showed an average somatic mutation burden of 2 to 6 mutations per megabase per cell, displaying signatures of ultraviolet radiation exposure. Positively selected driver mutations, including major drivers of cutaneous squamous cell carcinoma, were identified in 18% to 32% of normal epidermal cells at a density of approximately 140 driver mutations per square centimeter. Clonal expansion sizes and driver profiles varied across genes and individual donors.
Why it matters
This study demonstrates that cancer-driver mutations and clonal competition are pervasive in aged, sun-exposed human tissue well before any histological or clinical signs of malignancy appear.
Limits
The sample was restricted to eyelid epidermis from only four individuals, limiting generalizability to other anatomical sites, younger populations, or diverse skin phenotypes. Clinical outcomes and progression rates to skin malignancies were not tracked.
Cited by
- supports Genetic sequencing of healthy individuals reveals driver gene mutations in normal cells that do not exhibit dysregulated cell growth.