Several successive genetic alterations have been identified that underlie the progression of melanoma from benign nevus to invasive malignancy, with different melanoma subtypes showing distinct evolutionary trajectories, according to a report published online Nov. 12 in the New England Journal of Medicine.
This discovery can serve as the basis for formulating refined criteria for diagnosing melanoma and predicting its clinical course. It also “revealed an intermediate category of melanocytic neoplasia, characterized by the presence of more than one pathogenic genetic alteration – a finding that helps to resolve the decades-long controversy about dysplastic nevi,” wrote A. Hunter Shain, Ph.D., of the departments of dermatology and pathology and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, and his associates.
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Many of the pathogenic mutations in melanoma have already been catalogued, but the order in which they occur has never been defined before. “An individual tumor cannot be readily studied as it progresses from benign to malignant,” the investigators explained.
They approached the problem by comparing tissue samples from individual melanomas and melanoma precursor lesions across a spectrum of pathologic levels in different patients. They analyzed 37 melanocytic neoplasms archived at UCSF, St.John’s Hospital in London, and University Hospital Zurich, microdissecting 150 distinct areas of these samples for genetic sequencing. Eight dermatopathologists independently categorized the samples histologically as probably benign, intermediate but probably benign, intermediate but probably malignant, or malignant melanoma.
The investigators discovered “a more or less consistent pattern of genetic changes.” In every case, a single mutation was identified as the putative initiating oncogene. These were always mutations already known to activate the MAPK signaling pathway, usually in the BRAF or NRAS genes.
More advanced lesions harbored a broader spectrum of additional mutations that contributed to progression. Often these mutations affected the TERT promoter region, the CDKN2A gene and similar genes encoding particular protein subunits, or the tumor-suppressor ARID1A gene. A total of 77% of the areas examined in these intermediate tumors and melanomas in situ harbored TERT promoter mutations, which indicates that these mutations occur “at an unexpectedly early stage of the neoplastic progression,” Dr. Shain and his associates said (N Engl J Med. 2015 Nov 12. doi: 10.1056/NEJMoa1502583).
Only invasive melanomas were characterized by loss of both copies of the CDKN2A gene. Similarly, mutations in the SWI/SNF chromatin remodeling genes emerged primarily at the invasive stage. And losses in the PTEN and TP53 genes occurred exclusively in the thickest invasive melanomas, implying that these mutations occur late in the process of tumor progression. In addition, melanocytic neoplasms transitioned from linear to branched evolution only at later stages of progression, they said.
The investigators noted that “the existence of a category of lesions residing between clearly benign and clearly malignant states has long been proposed, but has remained controversial.” This study demonstrates that these intermediate neoplasms not only exist, but also carry discrete genetic alterations. “Detailed follow-up studies will be necessary to specifically delineate their histopathological characteristics and determine whether genetic or morphologic features can be identified that determine the risk of their progression to melanoma,” they added.
This study was supported by the National Institutes of Health and the Gerson and Barbara Bass Bakar Distinguished Professorship in Cancer Research. Dr. Shain reported having no relevant financial disclosures; one of his associates reported receiving grant support and personal fees from Novartis, Bristol-Myers Squibb, Roche, GlaxoSmithKline, Merck Sharp & Dohme, and Amgen.