Normal human skin cells harbor a surprisingly large number of un-inherited mutations that crop up over time, including many known cancer-promoters that help to drive tumor growth, researchers say.
These new findings reveal that so-called driver mutations, which are known to accumulate in certain skin cancer cells, also occur frequently in normal, sun-exposed skin cells.
They provide insights into the earliest stages of cancer development and raise important questions about the events that transform normal skin cells into cancer cells.
ñigo Martincorena and colleagues studied excess skin that was removed from the eyelids of four patients, aged 55 to 73, during a routine plastic surgery operation. The researchers took 234 small biopsies of this skin and sequenced the genomes of its cells, looking for mutations in genes that have been implicated in different types of cancer.
Martincorena et al. identified patterns of mutations associated with exposure to ultraviolet light, noting that the burden of such mutations was often higher in normal skin cells than it is in many skin cancer cells.
The researchers then devised a method to determine which of the acquired, or somatic, mutations in the healthy skin cells might stick around and drive cancer.
Their results suggest that many mutations that are known for driving cutaneous squamous cell carcinoma, including those affecting NOTCH genes and P53, are already under strong positive selection in normal skin cells. And, overall, the researchers suggest that more than 25% of normal, sun-exposed skin cells carry at least one of these driver mutations -- and that every square centimeter of skin contains hundreds of cancerous clones, competing to pass on their genes.
A Perspective article by Douglas Brash highlights these findings.