Genetic imputation of transcriptome and proteome illuminates novel therapeutic targets of cutaneous melanoma.

Genomic heterogeneity in melanoma tumors remains a major obstacle to achieving durable responses with conventional and targeted therapies. In this study, we performed a genome-wide association study meta-analysis, integrated with proteome-wide Mendelian randomization and colocalization analyses, to identify potential therapeutic targets for cutaneous melanoma (CM). Analyzing data from 5527 CM cases and 645 797 controls, we uncovered seven novel genome-wide significant variants linked to CM risk. Additionally, genetically predicted protein levels revealed 15 proteins associated with CM susceptibility, among which ASIP, CD72, CCL11, LYZ, and CCL25 showed the strongest associations. Validation in independent cohorts further supported their potential as biomarkers. Notably, these protein-coding genes are predominantly expressed in macrophages, B cells, CD8 T cells, and malignant cells within CM tissue. Among them, CD72 and LYZ stand out as promising candidates for therapeutic repurposing. These findings enhance our understanding of CM-related genetic and protein biomarkers, providing a foundation for future therapeutic development.