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Certain genetic alterations unique to melanoma lesion stage
Researchers have defined the succession of genetic alterations during melanoma progression, which showed specific evolutionary trajectories for different melanoma subtypes, according to study results published in The New England Journal of Medicine.
Specifically, researchers identified an intermediate category of melanocytic neoplasia, characterized by the presence of more than one pathogenic genetic alteration and distinct histopathological features. They also confirmed ultraviolet (UV) radiation as a major factor in the initiation and progression of melanoma.
“Cancer arises through the accumulation of genetic alterations that lead to unrestrained cell proliferation,” Boris C. Bastian, MD, PhD, professor of dermatology and pathology at University of California, San Francisco, and colleagues wrote. “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.”
Despite the large-scale cataloguing of the pathogenic mutations associated with melanoma, little study has been conducted on the order of occurrence.
Thus, Bastian and colleagues sequenced 293 cancer-relevant genes in 150 areas of 37 primary melanomas, as well as their adjacent precursor lesions. The histopathological spectrum of these areas included unequivocally benign lesions, intermediate lesions and intraepidermal or invasive melanomas.
The researchers observed that mutations of genes that are known activators of the mitogen-activated protein kinase pathway initiated precursor lesions.
Unequivocally benign lesions harbored BRAF V600E mutations exclusively, whereas lesions categorized as intermediate carried NRAS mutations and other driver mutations.
Further, 77% of areas of intermediate lesions and melanomas in situ harbored TERT promoter mutations, which indicated that these mutations are selected at an unexpectedly early stage of the neoplastic progression.
According to the researchers, biallelic inactivation of CDKN2A occurred exclusively in invasive melanomas, whereas PTEN and TP53 mutations occurred only in advanced primary melanomas.
The point-mutation burden increased from benign through intermediate lesions to melanoma; a strong signature of the effects of UV radiation remained detectable at each evolutionary stage.
Copy-number alterations became prevalent only in invasive melanomas, and tumor heterogeneity became apparent in the form of genetically distinct subpopulations as melanomas progressed.
“Our study … can serve as the foundation for formulation of refined criteria for diagnosis and prognostication,” Bastian and colleagues wrote. “It 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.” – by Cameron Kelsall
Disclosure: Bastian reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.