New research that traces melanoma's genetic progression shows that different lesion types have distinctive mutations. The study also bolsters the evidence for an intermediate category of lesions between benign nevi and malignant disease.

The process by which some benign skin lesions, or nevi, transform into melanomas remains unclear. A new study illuminates the genetic evolution of melanoma and strengthens the case for a controversial category of intermediate lesions that are midway between nevi and melanomas [N Engl J Med 2015;373:1926–36].

In this study, Boris Bastian, MD, PhD, of the University of California, San Francisco, and colleagues analyzed 37 melanoma samples—each including malignant tissue and its precursor lesion—and identified 150 distinct areas that represented different stages of disease progression. They asked eight pathologists to independently classify these areas as benign, intermediate but likely benign, intermediate but likely malignant, or melanoma. Although the pathologists usually agreed on areas at the benign and melanoma ends of the spectrum, they often disagreed on areas that were in the middle.

To find out if these histologic categories carried different genetic alterations, the researchers sequenced 293 cancer-causing genes in the melanoma samples. They observed that lesions unanimously classified by the pathologists as benign had only one driver mutation, BRAF V600E. Mutations in CDKN2A and genes that encode members of the SWI/SNF complex, such as ARID1A, occurred later, followed by mutations in TP53 and PTEN.

This analysis also shed light on whether intermediate lesions represent a separate category or whether they reflect the limitations of pathologists' ability to discriminate lesion types. Bastian and colleagues found that lesions classified by at least two pathologists as intermediate were genetically distinct. Unlike benign nevi, they carried TERT mutations and either NRAS mutations or the BRAF V600K alteration.

“Our study shows that there is something between benign and malignant,” says Bastian, adding that testing for these mutations could provide a better way to distinguish such lesions. “It's a step toward an objective diagnosis of melanoma,” he says.

Essentially, lesions can follow several pathways to become melanomas, the researchers propose. Alterations that activate the MAPK pathway—BRAF V600E, BRAF V600K, or NRAS mutations—are the earliest to emerge. TERT mutations then switch on telomerase and enable the lesions to escape replicative senescence. By the time lesions have progressed to invasive melanomas, they've accrued CDKN2A mutations that disable the G1-S cell-cycle checkpoint.

“I think this is a landmark paper for melanoma,” says David Polsky, MD, PhD, of the New York University Langone Medical Center in New York City, who wasn't connected to the study. “Here, they show that there is an intermediate stage in tumor development.”

“It adds to our knowledge of the molecular events that are occurring as some melanomas develop from nevi,” says Douglas Grossman, MD, PhD, of the University of Utah Health Sciences Center in Salt Lake City.

However, before any of the mutations could be clinically useful, Grossman cautions, researchers need to determine which ones influence outcomes for patients. –Mitch Leslie

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