Distinct Evolutionary Trajectories Reported for Different Melanoma Subtypes

Genetic evolution of melanoma

A study published on 12 November 2015 in The New England Journal of Medicine defines the succession of genetic alterations during melanoma progression, showing distinct evolutionary trajectories for different melanoma subtypes. It identified an intermediate category of melanocytic neoplasia, characterised by the presence of more than one pathogenic genetic alteration and distinctive histopathological features. The study implicated ultraviolet radiation as a major factor in both the initiation and progression of melanoma.

A total of 37 formalin-fixed, paraffin-embedded (FFPE) melanocytic neoplasms, enriched for melanomas with histologically distinct precursors, were retrieved from the archives of the Dermatopathology Sections of the University of California, San Francisco; St. John’s Hospital in London; and the University Hospital of Zurich. In total, 150 distinct areas were manually microdissected for sequencing. Each area was independently assessed by eight dermatopathologists and grouped into one of the following histologic categories: benign, intermediate but probably benign, intermediate but probably malignant, or melanoma. The American Joint Committee on Cancer staging system was used to further stratify melanomas.

The researchers sequenced in this study 293 cancer-relevant genes. They explained in the study background that the pathogenic mutations in melanoma have been largely catalogued; however, the order of their occurrence is not known. Large-scale sequencing projects that catalogue mutations in melanoma have been carried out mostly on advanced tumours, so it is difficult to infer the order of mutations.

Melanomas often arise from distinctive precursor lesions such as melanocytic nevi, intermediate lesions, or melanoma in situ, which makes the analysis of their progression possible.

Somatic mutations in dominant melanoma oncogenes such as BRAF, NRAS, GNAQ, or GNA11 and rearrangements resulting in fusion kinases are already present in benign nevi, indicating that they occur early during progression. However, little is known about the sequential order of additional mutations that are present in late-stage melanomas, including mutations of TERT, CDKN2A, TP53, genes encoding SWI/SNF subunits, and PTEN, among others.

There has been a long-standing debate about the existence of an intermediate category of lesions between clearly benign nevi and melanoma. This is exemplified by the concept of dysplastic nevi, which has remained controversial.

Delineating the order of genetic alterations that lead to primary melanomas and linking their emergence to specific progression stages of the primary lesion could yield biomarkers that would improve diagnosis and prognostication. The study authors explained that a better understanding of the genetic evolution of melanoma could also clarify the existence of intermediate lesions, because they would be predicted to have more pathogenic mutations than benign lesions but fewer than unequivocal melanomas.

The study team reports next findings:

  • Precursor lesions were initiated by mutations of genes that are known to activate the MAPK pathway.
  • Unequivocally benign lesions harbored BRAF V600E mutations exclusively, whereas those categorised as intermediate were enriched for NRAS mutations and additional driver mutations.
  • A total of 77% of areas of intermediate lesions and melanomas in situ harbored TERT promoter mutations, a finding that indicates that these mutations are selected at an unexpectedly early stage of the neoplastic progression.
  • Biallelic inactivation of CDKN2A emerged exclusively in invasive melanomas.
  • PTEN and TP53 mutations were found only in advanced primary melanomas.
  • The point-mutation burden increased from benign through intermediate lesions to melanoma, with a strong signature of the effects of ultraviolet radiation detectable at all evolutionary stages.
  • Copy-number alterations became prevalent only in invasive melanomas.
  • Tumour heterogeneity became apparent in the form of genetically distinct subpopulations as melanomas progressed.

The study was funded by the US National Institutes of Health and the Gerson and Barbara Bass Bakar Distinguished Professorship in Cancer Research.


Shain AH, Yeh I, Kovalyshyn I, et al. The Genetic Evolution of Melanoma from Precursor Lesions. N Engl J Med 2015; 373:1926-1936. DOI: 10.1056/NEJMoa1502583