Normal skin, which is often exposed to ultraviolet light throughout a person&’s life, contains many potential disease-causing mutations clustered within a narrow range of at least six cancer-associated genes, according to an analysis published on 21 May in Science.
Researchers from the Wellcome Trust Sanger Institute in the UK and their colleagues examined samples of cancer-free eyelid skin and found hundreds of clonal populations — which arise from these cells in normal tissue — peppered throughout. The study provides an initial glimpse of the mutational burden accumulated in normal tissue exposed to a known carcinogen — UV light. “This is a more important paper than it appears at first glance,” said Douglas Brash, a Yale biophysicist who penned an accompanying editorial.
One lesson from this work, he said, was that mutations in the skin were organised within clones from a single mutant cell, and that the genes that conferred a growth advantage were those that controlled stem cell fate. Using a technique that can capture even rare mutations, the team sequenced the exons of 74 genes that linked to skin and other cancers, as well as the full genome of one biopsy sample.
The researchers chose to sample skin cells partly because there was prior evidence that normal skin contains clones of cells with mutations in the tumor suppressor gene p53. They found a high mutational burden — about five mutations per megabase — similar to that of some cancers. There were around 140 positively selected driver mutations in the six focus genes per centimetre squared.
The researchers also estimated the clonal expansion size associated with the identified driver mutations. Surprisingly, the magnitude of clonal expansion of these driver mutations was only about 50 per cent greater than that of cells carrying only passenger mutations. The results also raise questions on the effect of age on the mutational burden of skin cells, including why cancer driver mutations might accumulate — or even accelerate — with age.