Regular exposure to the sun’s Ultraviolet UV rays can cause DNA mutations that lead to skin cancer, new research reveals that inflammation from chronic skin injury can trigger cancer-causing mutations. The researchers was led by scientists at UC San Francisco and Thomas Jefferson University in Philadelphia, in collaboration with Santa Cruz-based Nantomics LLC.

Understanding this previously invisible driver of tumor formation could lead to a new class of therapies for a variety of cancers. Previous studies of patients with head and neck cancers have suggested a link between tissue inflammation and cancer, but the specific mechanism behind this link is elusive.

Researchers studied the cells of children with a rare skin disorder- recessive dystrophic epidermolysis bullosa (RDEB). Patients with RDEB, sometimes called “butterfly children” because their skin’s extreme fragility calls to mind a butterfly’s wings, lack the connective protein collagen, which makes their skin prone to blistering and scarring at the slightest touch. In addition to severe pain and potential disfigurement, patients also frequently develop aggressive squamous cell cancer in injured areas.

The researchers sequenced the entire protein-coding part of the genome in these samples, which enabled them to detect subtle patterns of DNA mutation across the genome in inflamed and cancerous tissue that were clearly distinct from the types of mutational signatures caused by UV radiation. The researchers showed that this pattern of mutation is caused by a protein- APOBEC, which normally plays a role in adding diversity to cellular proteins and is also thought to defend against viruses.

In RDEB patients, APOBEC appears to become overly active as a consequence of chronic tissue inflammation, causing it to introduce mutations across the genome, some of which eventually lead to cancer. Using a computational approach, the researchers ruled out problems with DNA repair, which is a common driver of increased levels of mutation in many cancers.

Patterns of mutation density throughout the genome of RDEB tissue samples indicated that normal DNA repair mechanisms were functioning properly, confirming that the cancer-causing mutations in RDEB patients were as a result of inflammation and dysfunctional APOBEC alone.
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