An international team of scientists has mapped out the genetic trajectories taken by melanoma as it evolves from early skin lesions (precursors) to malignant skin cancer, which can be lethal when it invades other tissues in the body.

By tracing the genetic changes that take place over time in the development of the disease, the findings reaffirm the role of sun exposure in the emergence of precursor lesions, such as the common moles known as nevi, but also suggests that continued ultraviolet radiation (UV) damage to benign precursor lesions may push them on a path toward malignancy.

More significantly, the study provides new evidence that genetic and cellular characteristics of skin lesions that are neither clearly benign moles nor malignant melanoma place those lesions in a distinctive intermediate category, the existence of which has been hotly debated among dermatologists and pathologists.

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“What happens to patients now is totally unstandardized,” said senior author Boris Bastian, MD, PhD, the Gerson and Barbara Bass Bakar Distinguished Professor of Cancer Research at the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC). “Some doctors consider these ‘intermediate’ types of lesions to be entirely benign, or shave off only part of the lesion and leave some behind. But others treat it as an early melanoma. This work should open the door to understanding how risky these lesions are and when they should be completely removed.”

When a melanoma is diagnosed, its precursor lesion is sometimes still present on the skin adjacent to the cancer. As reported in The New England Journal of Medicine (doi:10.1056/NEJMoa1502583), the research team took advantage of this unique feature of the disease to identify the genetic differences between precursors and melanoma.

Led by A. Hunter Shain, PhD, a postdoctoral fellow in the Bastian laboratory and HDFCCC member, the scientists gathered skin samples containing both precursor lesions and melanoma that had been obtained from 37 patients, then sequenced 293 cancer-causing genes in 150 distinct areas micro-dissected from those samples.

In a study designed to determine how genetic analysis would align with standard techniques used in melanoma diagnosis, 8 pathologists specializing in skin disease microscopically examined each of the 150 areas independently. The pathologists assigned each area to 4 main categories ranging from benign to invasive melanoma based on their judgments of how far the cells in each area had progressed toward malignancy.

Intriguingly, in all of the 13 areas that were unanimously assessed as benign by the pathologists, the researchers found only a single pathogenic mutation, BRAF V600E, which has long been associated with melanoma. Based on these data, this single alteration in the BRAF gene appears to be sufficient for the formation of a nevus.

“There’s good agreement between the pathologists’ assessments at the extremes of the spectrum, but less so with intermediate lesions,” said Shain. “On a genetic level, however, this work clearly shows that there are intermediate lesions. These things really exist; it’s not a binary situation.”

Mutations caused by UV damage have a distinctive genetic signature, and in another significant finding, the researchers observed this signature in cancer-causing genes at every stage of melanoma progression.

“Kids who are in the sunlight more tend to have a greater number of benign moles, and if they continue to stay in the sunlight, those moles are more likely to progress to melanoma,” Shain said. “This study shows that UV-radiation-induced mutations start to accumulate before a benign mole forms, and that UV-radiation-induced mutations continue to drive the progression of some benign and intermediate lesions towards melanoma. So exposing even benign moles to UV is not without risk.”