The dynamics of mutation rate, aging and extrinsic risk in melanoma development

The gradual accumulation of intrinsic mutations linked to cell division, and the mutational imprints caused by extrinsic or environmental factors on the genome, afford the opportunity to examine the relationship between intrinsic and extrinsic risk in cancer subtypes with varying lifetime incidences.
The incidence of the distinct molecular subtypes of cutaneous melanoma varies depending on anatomical site, intensity and pattern of ultraviolet (UV) light exposure, and age. Cutaneous melanoma has been subdivided into four groups, with tumor groups defined by driver mutations in either BRAF, NRAS, or NF1; with the final group defined by the absence of mutations in these genes (triple wild-type).
Here we analyze the relative contributions of intrinsic risk, measured by characteristic age-related (clock-like) mutations, and extrinsic risk, measured by canonical UV light-induced signatures, to tumor development in melanoma subtypes. We show that the contributions of intrinsic and extrinsic mutations differ in magnitude and chronology during the molecular evolution of the distinct disease subtypes. We observe a gradual decline in intrinsic cell division rates as patients’ age. Our analysis of UV light-driven mutations reveals that gradual UV damage drives non-BRAF melanomas, and punctuated UV damage is linked to BRAF melanomagenesis.
These data suggest that mutations accumulate at different rates in the disease subtypes, independently of germline melanoma susceptibility, from cells of origin with distinct proliferation rates. Based on our results we propose that models examining the relative roles of extrinsic and intrinsic risk in cancer consider subtype-specific lifetime risks, germline susceptibility and somatic mutational processes.