Dangerous mutations hide in healthy skin

Healthy skin can harbor a multitude of gene mutations that are known drivers of the dangerous skin cancer melanoma, according to a study published this week in Nature. The findings help explain how melanomas can arise suddenly and without any warning signs.

Jessica Tang, a researcher at UC San Francisco, set out to identify mutations in a rare population of cells in the skin, known as melanocytes. Melanocytes contain the skin-colorizing, protective pigment melanin. They are also the cells that develop into melanoma. Tang and colleagues found that roughly a fifth of healthy melanocytes have melanoma-causing mutations. Learning how mutations arise in these cells is critical for understanding how this deadly disease develops.

There are billions of cells in the human body. Each cell contains a copy of the entire genetic sequence. Mutations can happen naturally by chance or due to damage like exposure to ultraviolet light. Mutations cropping up in the wrong genes, though, can be dangerous. The outermost layer of the skin is thinner than the average human hair. Exposure to the sun’s UV rays through this thin layer can trigger cancer-causing mutations. Finding harmful mutations in cells from melanoma is expected. Finding them in their normal-appearing neighbors—is not.

Most surprising to the researchers was finding that the number of mutations in each cell differed based on how often skin was exposed to sunlight. Cells from skin that is usually protected from UV radiation, like the sole of the foot, showed the lowest mutation number, as one might expect. But in occasionally exposed skin, such as the back or the arms and legs, pigment cells had a higher number of mutations than those in skin that is frequently exposed, such the face or neck. The findings are consistent with the fact that melanomas are most often found on intermittently exposed skin. Figuring out why that is will require further research. This team also report that the number of mutations in normal skin located next to a tumor was higher than skin from a someone who was cancer-free. Doctors and researchers may be able to use melanocyte mutations as an indicator of cumulative sun damage and increased cancer risk.

The researchers managed to overcome a technical hurdle that complicates a lot of gene sequencing research. The most accurate sequencing methods require a large number of cells. Melanocytes, however, are rare and spread out in the skin. It’s impossible to take a biopsy. To overcome this, the team took a small number of melanocytes from skin and grew them in the lab to let them multiply until there were enough to properly sequence.

Using this simple but elegant technique, Tang and her team were able to “offer an unprecedented view of…mutations in normal melanocytes,” Inigo Martincorena explained in Nature Briefing.

The study’s results accord with previous reports of cancer-driving mutations appearing in tissues free of cancer. In 2015, Martincorena’s team detected cancer-causing mutations in samples of healthy eyelid skin. They found that more than a quarter of normal cells carried harmful mutations1. The same year, a group based at the Dana-Farber Cancer Institute in Boston described the accumulation of mutations during the normal aging process in healthy people. The mutations they detected were similar to those found in people with blood cancers2. Conventional wisdom in cancer research assumed that these mutations would be limited to cancer cells.

It now seems clear that health professionals are going to need in-depth knowledge of what normal-appearing skin can hide to better detect and prevent melanoma in its earliest stages. Detection used to rely on finding noticeable changes to the skin, such as the growth of an irregular mole. Doctors and researchers are now finding that these tumors often appear without warning3. The work done by Tang and her colleagues hints at why this is. Melanocytes may become primed with early mutations that only give rise to melanoma after acquiring further mutations. For melanoma, and perhaps many other cancer types, underestimating the danger of tissues that look normal could have serious consequences.

1.     Martincorena I, Roshan A, Gerstung M, Ellis P, Van Loo P, McLaren S, Wedge DCFullam A, Alexandrov LB, Tubio JM, Stebbings L, Menzies A, Widaa S, Stratton MR, Jones PH, Campbell PJ. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science. 2015 May 22;348(6237):880-6. doi: 10.1126/science.aaa6806. PMID: 25999502; PMCID: PMC4471149.

2.     Steensma, D. P., Bejar, R., Jaiswal, S., Lindsley, R. C., Sekeres, M. A., Hasserjian, R. P., & Ebert, B. L. (2015). Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood, 126(1), 9–16. https://doi.org/10.1182/blood-2015-03-631747

3.     Shitara D, Nascimento MM, Puig S, Yamada S, Enokihara MM, Michalany N, Bagatin E. Nevus-associated melanomas: clinicopathologic features. Am J Clin Pathol. 2014 Oct;142(4):485-91. doi: 10.1309/AJCP4L5CJGKTJVDD. PMID: 25239415.