The landscape of gain and loss of function mutations in melanoma

Abstract Melanoma is a common and aggressive cancer, with a rising incidence in most developed countries. Major discoveries in melanoma biology have been rapidly translated, allowing cures for some late-stage patients. Despite these advances, incomplete knowledge of genes and pathways that are gained or lost during melanogenesis prohibits cures for many patients. To identify gain-of-function and loss-of-function drivers of melanoma, we established a multi-omics cohort of melanoma patient-derived xenografts. By linking mutations with gene and protein expression, we characterize gain or loss-of-function of specific melanoma drivers in treatment refractory tumor models. We use multi-omics integration and structural-context representation to distinguish gain from loss of function variants, revealing new candidate melanoma genes and targets. This study provides a comprehensive resource of tumor models with the genetic, molecular and structural features of gain and loss of function melanoma drivers, allowing future development of better therapeutics for this devastating and heterogenous malignancy.