Melanoma subtypes have different evolutionary paths

June 1, 2016

Recent research supports UV radiation as the major driving force in the initiation and progression of melanoma, and the same investigation demonstrated different paths of evolution for various melanoma subtypes.

There has been a controversy over whether there is an "intermediate stage" lesion between nevi that are clearly benign (D10) and clearly malignant (C43), and a recent paper demonstrates that there is, in fact, an intermediate stage.

Speaking here at the 10th annual Canadian melanoma conference, Whistler, British Columbia, Canada, recently, Boris Bastian M.D., professor, departments of  dermatology and pathology, executive director, Clinical Cancer Genomics Laboratory, Gerson & Barbara Bass Bakar Distinguished Professor of Cancer Biology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, Calif., notes that there has historically been much disagreement about melanoma precursor lesions and the degree of dysplasia or atypia in different patients.

"There are clinical and histologic definitions (about dysplastic nevi) that not always correlate for individual lesions,"  Dr. Bastiansays. "Even among histologic definitions, there are variations. Some (pathologists) may grade (nevi) from low grade to moderate to severe dysplasia. Other pathologists do not agree. There is not good concordance."

Factors that dermatologists consider in looking at melanoma  risk in primary prevention include the overall number of nevi that a patient has, the quality of the nevi, and the size of the nevi, according to Dr. Bastian.

Dr. Bastian cites a landmark study, involving 716 patients concluded that the presence of one clinically dysplastic nevus is linked to a two-fold increased risk of melanoma and 10 or more clinically dysplastic nevi were associated with a 12-fold elevated risk in melanoma. The study demonstrated that in the absence of dysplastic nevi, greater numbers of small nevi were linked to a roughly two-fold increased risk of melanoma and greater numbers of both small and large non-dysplastic nevi were linked to a four-fold increased risk of melanoma.1

A National Institutes of Health consensus conference was held where it was proposed that dysplastic nevi be referred to as atypical nevi. "Questions like 'do they exist (dysplastic nevi)?' and 'what are they?' can't be answered by just looking at them clinically or under the microscope," explains Dr. Bastian. "It is because there have not been good ways to measure the nevi and the degree of dysplasia." 2

To address the lack of consensus on a clinical and histopathologic level, Dr. Bastian and colleagues sought to explore how melanomas evolve from precursor lesions including dysplastic nevi. Dr. Bastian and colleagues sequenced 293 cancer-relevant genes in 150 different areas of 37 primary melanomas that had an adjacent precursor lesion. The areas included benign lesions, intermediate lesions, and intra-epidermal lesions or invasive melanomas.3

"We wanted to look at them from the molecular aspect under the assumption that melanoma is caused by genetic alterations that accumulate over time," says Dr. Bastian. "It is well-established that if you sequence advanced melanomas, you will find multiple pathogenic mutations that disrupt different key signalling pathways."

Dr. Bastian and colleagues found that all 13 areas that were unanimously considered to be benign possessed only a BRAF V600E mutation as the only apparent pathogenic mutation. When looking at 19 of 21 areas categorized as intermediate, Dr. Bastian and co-investigators identified possessed multiple pathogenic mutations. Most of the intermediate lesions had genetic characteristics that fall somewhere between benign and malignant neoplasms.3

"We believe that the BRAF V600E mutations occur relatively early," notes Dr. Bastian. "In the first or second decade of life, you get most common nevi, which frequently already carry the BRAF V600E  mutation. For some reason, it seems that the incidence of melanocytic neoplasms with BRAF V600E mutation drops later in life. It therefore seems that there may be a particular state of vulnerability (early in life) for lesions initiated by this mutation."

In contrast, melanomas that contain NRAS and BRAF V600K or K601E mutations occur in skin of older patients that has been chronically sun-damaged. Lesions that are regarded as intermediate and melanomas in situ possess TERT promoter mutations.

Another key finding from the study confirms the pathogenic role of ultraviolet radiation (UV) for melanomas on the sun-exposed skin. "The study demonstrates that ultraviolet radiation is the main exogenous factor that makes nevi progress to melanoma," says Dr. Bastian. "It is the driving force that turns precursors into melanomas. The numerous new mutations that cells of the precursor lesion accumulated as they evolved to melanoma have a very strong UV signature."

The finding further underlines the importance of individuals using sunscreens and/or practicing sun-safe behavior, particularly if they are fairer-skinned. In addition, it highlights that exposing benign nevi to the sun is risky, too.

The investigators have shown how melanomas evolve from precursor lesions through the accumulation of mutations in the genome. "Mutations arise sequentially and not all at once," explains Dr. Bastian. "We have shed light on the order in which they arise."

Mutations that are found less frequently, such as in the genes PTEN and TP53, seem to arise later in life as primary melanomas, once they are invasive and have become thicker, notes Dr. Bastian.

Disclosure: Dr. Bastian reports no relevant conflicts of interest.


1 Tucker MA, Halpern A, Holly EA, et al. Clinically recognized dysplastic nevi. A central risk factor for cutaneous melanoma. JAMA.          1997;277(18):1439-44.

 2Consens Statement. 1992;10(1):1-25. Diagnosis and treatment of early melanoma. NIH Consensus Development Conference. January 27-29,      1992.

3Shain AH, Bastian BC. The Genetic Evolution of  Melanoma. N Engl J Med. 2016;374(1):995-6.