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Melanoma's genetic trajectories: research provides clearer picture

An international team of researchers has mapped out the genetic trajectories taken by melanoma as it evolves from precursors to malignant skin cancer. Their findings were published in The New England Journal of Medicine (Nov. 12, 2015).

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

Led by A. Hunter Shain, PhD, a postdoctoral fellow and a University of California San Francisco Helen Diller Family Comprehensive Cancer Center (HDFCCC) member, the scientists gathered skin samples containing both precursor lesions and melanoma that had been obtained from 37 patients, and they then sequenced 293 cancer-causing genes in 150 distinct areas micro-dissected from those samples.

Each of these 150 areas was independently examined by pathologists and assigned four main categories: benign, probably benign, probably malignant, and invasive melanoma.

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. In invasive melanomas genetic analysis were found to contain a large number of point mutations affecting many genes, as well as a significant number of copy-number alterations.

The genetics of intermediate lesions presented in most cases with BRAF mutations, and were accompanied by additional pathogenic mutations, but not the full set observed in invasive melanoma. In particular, many BRAF mutations in the intermediate lesions were accompanied by mutations in the TERT gene.

Intermediate lesions do exist

While the researchers found more point mutations in intermediate lesions than in benign moles, there were far fewer point mutations in intermediate lesions than in invasive melanomas, and copy-number alterations were rare. "On a genetic level, . . . this work clearly shows that there are intermediate lesions. These things really exist—it is not a binary situation,” said Dr. Shain in a press release.

Mutations caused by UV damage have a distinctive genetic "signature," which was present at every stage of melanoma progression. According to Dr. Shain, the study's findings on UV-induced mutations provides additional grounding to well-documented aspects of melanoma epidemiology.

"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," Dr. 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."

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