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Post-mortem Melanocyte Mutations Provide Melanoma Clues

NEW YORK – Seemingly normal skin samples may contain cutaneous melanoma-related mutations that may be missed by focusing on risky-looking naevi, or moles, according to a new study focused on ultraviolet light-linked DNA damage patterns.

"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," senior and corresponding author Hunter Shain, a dermatology and cancer researcher at the University of California at San Francisco, said in a statement.

For a paper published in Nature on Wednesday, Shain and his colleagues used targeted DNA sequencing, exome sequencing, single-cell genotyping, or RNA sequencing to assess flow cytometry-sorted melanocyte cells in more than 100 post-mortem skin samples collected at sites from half a dozen deceased individuals with European ancestry between the ages of 63 and 85 years old. They noted that two individuals had a history of melanoma, while four had been skin cancer-free, and the samples considered came from parts of the body with more or less sun exposure.

"Melanoma is an endpoint most often seen only after decades of mutational damage, but some people are at greater risk than others," Shain explained. "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."

Somewhat counter-intuitively, the team saw a rise in melanocyte mutational burden in cells from skin sites such as an individual's back that are exposed to the sun somewhat infrequently, compared to melanocytes in skin samples from as a person's face and other parts of the body that see a lot of sun.

"The findings of lower mutation burdens in chronically sun-exposed sites deserves further study, as it indicates possible differences in mutation rate, DNA repair, or turnover among melanocytes from these anatomic sites," the authors reported, adding that "our observations are consistent with the fact that melanomas are disproportionately common, compared to other forms of skin cancer, on intermittently sun-exposed skin."

The sequence data also uncovered an uptick in melanocyte mutational burden in samples taken from sites sitting next to known skin cancers relative to melanocyte samples from individuals who did not have skin cancer, they explained, hinting that "the mutation burden of normal skin can be used to measure cumulative sun damage and risk of skin cancer."

Likewise, the researchers saw examples of healthy skin samples that harbored pathogenic mutations, though they appeared to lack the oncogenic oomph to prompt skin cancer development without the presence of additional alterations. When they took a look at phylogenetic patterns across the broader set of melanocytes, meanwhile, they uncovered groups of clonal skin cells sharing similar alterations that seemed to move together in the skin.

Based on these and other results, the authors suggested that "human skin is peppered with individual melanocytes or fields of related melanocytes that contain pathogenic mutations that drive melanoma. These poised melanocytes are likely to give rise to melanomas that appear in the absence of a pre-existing naevus, once additional mutations are acquired."