Molecular subtype, biological sex and age shape melanoma tumour evolution

Many cancer types display sex and age disparity in incidence and outcome. The mutational load of tumours, including melanoma, varies according to sex and age. However, there are no tools to explore systematically whether clinical variables such as age and sex determine the genomic landscape of cancer.

To establish a mathematical approach using melanoma mutational data to analyse how sex and age shape the tumour genome.

We model how age-related (clock-like) somatic mutations that arise during cell division, and extrinsic (environmental ultraviolet radiation) mutations accumulate in cancer genomes.

Melanoma is driven primarily by cell-intrinsic age-related mutations and extrinsic ultraviolet radiation-induced mutations, and we show that these mutation types differ in magnitude and chronology and by sex in the distinct molecular melanoma subtypes. Our model confirms that age and sex are determinants of cellular mutation rate, shaping the final mutation composition. We show mathematically for the first time how, similarly to noncancer tissues, melanoma genomes reflect a decline in cell division during ageing. We find that clock-like mutations strongly correlate with the acquisition of ultraviolet-induced mutations, but critically, men present a higher number and rate of cell-division-linked mutations.

These data indicate that the contribution of environmental damage to melanoma likely extends beyond genetic damage to affect cell division. Sex and age determine the final mutational composition of melanoma.