Melanoma, the deadliest skin cancer, can come out of nowhere—or so it may seem. After all, just 30% of melanomas arise from preexisting moles. More often, melanomas emerge from “normal” melanocytes that have accumulated DNA damage over years of exposure to the sun’s ultraviolet rays. Although this damage isn’t obvious to the eye, it can be measured. More to the point, it can be correlated with melanoma risk, long before cancer has a chance to bloom.

The possibility of screening individuals for skin cancer’s mutational seeds has been explored by scientists based at the University of California, San Francisco. They sequenced melanocyte DNA in skin samples, one cell at a time, to tally mutations, with an emphasis on a handful of mutations that are the main drivers of the emergence and growth of melanoma.

The samples came from six individuals, two melanoma survivors and four cadavers of persons never afflicted by melanoma. All were white. The researchers analyzed DNA from a total of 133 melanocytes from the back, head, legs, shoulder, buttocks, and feet.

According to the researchers, melanocytes from normal skin near the melanoma in the former cancer patients had strikingly more mutations, including melanoma-associated mutations, than skin from the same sites in individuals who never had melanoma.

Details of this study appeared October 7 in Nature, in an article titled, “The genomic landscapes of individual melanocytes from human skin.”

“A complex set of risk factors is associated with melanoma, including cumulative levels of sun exposure, peak doses and timings of exposure throughout life, skin complexion, tanning ability, and DNA repair capacity,” the article’s authors observed. “It is nearly impossible to quantify and integrate the effects of each of these variables.”

Nonetheless, the article’s authors, led by senior author A. Hunter Shain, PhD, reported that they had developed a new method to directly measure the mutational damage in individual melanocytes. The new method is a blend of two old methods: single-cell sequencing (which requires error-prone genome amplification), and clonal expansion of single cells into colonies of thousand before sequencing (which is more reliable in terms of sequencing, but may rely on the ability of reluctant cells to thrive in culture).

“In summary, we implemented a series of experimental and bioinformatic solutions to overcome the major obstacles associated with genotyping individual melanocytes,” the authors reported. “One hundred and thirty-three melanocytes passed our quality control metrics, and were included in all subsequent analyses.”

The genomic methods used to probe skin damage in the new study could be developed to estimate baseline melanoma risk for individuals in the general population, and to make recommendations about how often someone should be screened for cancer by a dermatologist, Shain asserted.

“It turns out that a multitude of individual cells in so-called normal skin are riddled with mutations associated with melanoma, which are a result of sun exposure,” he said. “Melanoma is an endpoint most often seen only after decades of mutational damage, but some people are at greater risk than others. With the techniques we have developed, those who have the most accumulated mutations can be monitored more closely and can choose to better protect themselves from sun exposure.”

Melanoma arises in a type of skin cell called a melanocyte, the focus of the Nature study. Melanocytes make the pigment melanin, which helps protect skin cells, including the much more abundant keratinocytes, from sun damage. But melanocytes pose the greatest risk when DNA damage causes them to grow out of control.

According to the American Cancer Society, melanoma rates are rising. In 2020, about 100,000 people in the United States will be diagnosed with melanoma and about 6,850 will die.

Although more sun exposure leads to higher risk, the relationship is complex, Shain noted, and relates to skin tone, inherent DNA-repair capacity, and other factors. Childhood sunburns might pose greater risk than occupational exposures during adulthood, such as working outdoors. “Measuring mutations may be a good way to gauge the net effect of all these variables on melanoma risk,” Shain said.

Oddly, melanoma occurs more often on intermittently sun-exposed areas of the skin, such as the back or thighs, compared to chronically exposed areas, such as the face. Consistent with this pattern, Shain’s research team found more mutations in melanocytes from the back and limbs than in skin from the head and neck.

The single-cell analyses conducted in the study enabled a focus on the relatively sparse melanocytes in skin and identification of cells with precancerous mutations. “We anticipate,” Shain concluded, “that a streamlined, automated version of these methods will one day become widely available to gauge melanoma risk and could serve as the basis for cancer-screening recommendations.”

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