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Presentation

From Melanocyte to Melanoma: Taxonomy, Mutational Evolution, and the Impact of UV Exposure

Description

The talk explains how melanocytic neoplasms are classified by clinical subtype and disease stage, with emphasis on the major cutaneous melanoma groups defined by chronic sun damage: low cumulative sun damage (CSD) and high CSD. Low CSD melanomas typically arise on intermittently sun-exposed sites, often begin with BRAF V600E in a nevus, and accumulate additional driver events such as PTEN loss, TERT promoter mutations, CDKN2A loss, TP53 changes, and RQ2/other chromatin-related alterations. High CSD melanomas arise on chronically sun-exposed skin, have very high mutation burdens, and are commonly driven by MAP kinase pathway alterations such as NRAS or NF1 loss rather than BRAF V600E. The speaker describes sequencing melanomas and their precursor lesions to reconstruct progression, showing that many melanomas evolve from nevi or dysplastic nevi, but that “de novo” melanomas likely arise from a field of invisible, clonally related melanocytes already carrying some oncogenic mutations. Single-cell analyses of normal sun-damaged skin revealed unexpectedly high mutation burdens in melanocytes and frequent melanoma-driver mutations, suggesting normal skin contains many partially transformed cells. A study of heavy tanning bed users found their melanocytes had about twice as many mutations as controls, with a UV mutational signature and a subtle enrichment of a signature potentially related to tanning-bed UV exposure; 25% of their melanocytes carried pathogenic driver mutations, implying a large field effect. The talk concludes with acral melanoma, a rare subtype on palms, soles, and nail beds that is not primarily UV-driven and instead shows distinct genetics, including complex copy-number “hailstorm” alterations and early TERT activation, underscoring that melanoma evolution depends on both mutation order and the cell of origin.

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Conclusions

Melanoma development appears to require the accumulation of multiple somatic driver mutations, typically affecting several core pathways rather than a single defining lesion.
The order in which driver mutations arise helps determine whether a melanoma follows a low-CSD, high-CSD, or acral progression trajectory.
Low-CSD melanomas most often emerge from common nevi carrying an initiating BRAF V600E mutation followed by additional pathway alterations.
High-CSD melanomas frequently arise from intermediate or dysplastic precursor lesions that already harbor some driver mutations before full transformation.
Many melanomas that seem to arise de novo may actually originate from invisible fields of genetically altered melanocytes in otherwise normal-appearing skin.
Normal-appearing sun-exposed skin can contain melanocytes with surprisingly high mutation burdens and occasional bona fide melanoma driver mutations.
Extreme tanning bed use is associated with substantially increased mutation burden in melanocytes compared with matched controls and even older individuals.
Tanning bed exposure may also alter the spectrum of UV-induced mutations, suggesting a distinct mutagenic effect beyond natural sunlight.
A significant fraction of melanocytes from extreme tanning bed users carry pathogenic alterations, implying that whole-body UV exposure can create a broad field of premalignant cells.
Acral melanoma is biologically distinct from cutaneous melanoma, with different common drivers and a prominent role for complex copy-number changes or 'hailstorms'.
Acral melanoma cannot be defined reliably by anatomic site alone because some acral-site tumors share low-CSD-like, UV-associated features and genetics.
The cell of origin matters for melanoma evolution, with acral melanocytes on non-hair-bearing skin giving rise to a different disease course than cutaneous melanocytes.
Overall, integrating histopathology, genetics, and site of origin is necessary to understand and correctly classify melanoma subtypes.

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