Characterization of Pathogenic Mutations in Melanoma Progression


Key Points

  • A strong signature of ultraviolet radiation effects was detectable at all evolutionary stages of melanoma.
  • NRAS or BRAF V600K or K601E mutations were commonly associated with intermediate lesions or melanomas in situ that had accumulated other pathogenic mutations.

In a study reported in The New England Journal of Medicine, Shain et al identified the order of occurrence of mutations in the progression of melanoma as well as characterized point mutation burden and chromosomal instability during disease evolution.

Study Details

The study involved sequencing of 293 cancer-relevant genes in 150 areas of 37 primary formalin-fixed, paraffin-embedded melanocytic neoplasms and their adjacent precursor lesions. The sample was enriched for melanomas with histologically distinct precursors. The histopathologic spectrum of these areas included unequivocally benign lesions, intermediate lesions, and intraepidermal or invasive melanomas.

Emergence of Mutations

Precursor lesions appeared to be invariably initiated by gene mutations known to activate the MAPK signaling pathway, usually in BRAF or NRAS. All areas considered unequivocally benign had a BRAF V600E mutation as the only apparent pathogenic mutation. Those lesions considered intermediate exhibited multiple pathogenic mutations, including BRAF V600K or K601E and NRAS mutations.

Thus, melanomas with BRAF V600E mutations were found to arise from benign nevi, whereas NRAS or BRAF V600K or K601E mutations were more commonly associated with intermediate lesions or melanomas in situ that had accumulated other pathogenic mutations. Overall, 77% of areas of intermediate lesions and melanomas in situ exhibited TERT promoter mutations, suggesting that these mutations are selected at an early stage of disease progression.

Mutations in SWI/SNF chromatin remodeling genes were found predominantly in invasive melanomas, and biallelic inactivation of CDKN2A was observed exclusively in invasive melanomas. PTEN and TP53 mutations were uncommon and were found only in thicker, invasive melanomas.

Point Mutation Burden and Copy Number Alteration

Point mutation burden increased from benign through intermediate lesions to melanoma, with a strong signature of ultraviolet radiation effects observed at all evolutionary stages. In melanoma areas, the burden of point mutations was correlated with sun exposure, estimated by patient age and anatomic site and by solar elastosis.

Copy number alterations were rare in benign lesions, occasionally found in intermediate lesions and melanomas in situ, and invariably found in invasive melanomas. Tumor heterogeneity was evidenced in the finding of genetically distinct subpopulations as lesions progressed.

The authors noted: “In aggregate, these results suggest that ultraviolet radiation is a dominant mutagen in the pathogenesis of sun-exposed melanomas that acts throughout all stages of progression, starting with the initiation of precursor lesions, whereas chromosomal instability arises as an additional factor at the transition to the invasive stage.”

They concluded: “Our study defined the succession of genetic alterations during melanoma progression, showing distinct evolutionary trajectories for different melanoma subtypes. It identified an intermediate category of melanocytic neoplasia, characterized by the presence of more than one pathogenic genetic alteration and distinctive histopathological features. Finally, our study implicated ultraviolet radiation as a major factor in both the initiation and progression of melanoma.”

The study was funded by the National Institutes of Health and others.

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