The Genetic Architecture of Cutaneous Melanoma Across the Variant Spectrum

Cutaneous melanoma is an aggressive skin cancer with a predominant and rising incidence in fair-skinned populations. Here, we systematically characterized its genetic architecture across the allele-frequency spectrum and functional genomic landscape. We identified 126 susceptibility loci through a GWAS meta-analysis of 1,398,034 individuals, including 92 not previously reported. Spatially resolved mapping of heritability across 14 spatial transcriptomic samples revealed that heritability enrichment in melanocytes and the manifestation of inherited genetic effects are context-dependent, shaped by cellular functional states and spatial context, where infiltration and interactions of T cells contribute. Genome-wide rare-variant association analyses in 3,819 cases and 340,050 controls with whole-genome sequencing data from the UK Biobank, followed by replication in three independent cohorts, highlighted 10 protein-coding genes and an intergenic lncRNA (RP11-77B22.2) validated across cohorts. We further demonstrate the unique contributions of rare variants to heritability, risk prediction and clinical implications for genetic evaluation in early-onset patients. A biological network contextualizing interactions and regulatory relationships among genes prioritized across the variant spectrum revealed eight functional modules underlying disease biology. Together, our study provides insight into the biological and context-dependent mechanisms underlying cutaneous melanoma susceptibility, with implications for future translational research.