Mutations that drive cancer lurk in healthy skin

By late middle age, about a quarter of skin cells carry cancer-driving mutations caused by exposure to sunlight — and it’s perfectly normal.

Researchers had previously thought that the types of mutations that fuel tumor growth were rare and happened just before a cell becomes cancerous. But a study of the eyelids of four people who don’t have cancer reveals that such mutations “are staggeringly common in normal skin,” says Philip Jones, a clinical scientist at the University of Cambridge.

Jones and his colleagues collected 234 skin samples from four people ages 55 to 73 who had plastic surgery to correct droopy eyelids. DNA sequencing showed that about 20 percent of the skin cells had mutations in the NOTCH1 gene, the team reports in the May 22 Science. When mutated, that gene is a driving force in some cancers, including skin cancers called squamous cell carcinomas.

Other cancer-driving mutations were also present in the normal skin cells, sometimes with multiple mutations per cell. “What we see is not just a few, but many seeds of cancer already sown in that field,” says study coauthor Peter Campbell, a cancer geneticist at the Wellcome Trust Sanger Institute in Hinxton, England.

The findings suggest that the line between normal cells and cancer is fuzzy, says Douglas Brash, a skin cancer researcher at Yale University. “There’s really much more of a continuum than we thought.”

Some of the mutations gave skin cells a competitive advantage over other skin cells, the researchers found. Cells with mutations that don’t drive cancer formed patches of skin covering 0.15 square millimeters on average. Cancer-driving mutations in NOTCH1 or a second gene, TP53, grew into patches averaging 0.23 mm² and 0.33 mm². The expansion creates more area for ultraviolet light to do further damage that might tip cells into becoming cancerous.

It’s not all bad news, though, Jones says. Even with cancer-driving mutations, cell growth was kept in check and cells behaved like perfectly healthy skin, he says. “The optimistic view is that our skin is astonishingly good at dealing with the inevitable damage caused by sunlight.” Learning how the body reins in the cells’ growth could lead to improved cancer treatment.