Integrated molecular drivers coordinate biological and clinical states in melanoma

We performed harmonized molecular and clinical analysis on 1,048 melanomas and discovered markedly different global genomic properties among subtypes (BRAF, (N)RAS, NF1, Triple Wild-Type), subtype-specific preferences for secondary driver genes, and active mutational processes previously unreported in melanoma. Secondary driver genes significantly enriched in specific subtypes reflected preferential dysregulation of additional pathways, such as induction of TGF-β signaling in BRAF melanomas and inactivation of the SWI/SNF complex in (N)RAS melanomas, and select co-mutation patterns coordinated selective response to immune checkpoint blockade. We also defined the mutational landscape of Triple Wild-Type melanomas and identified enrichment of DNA repair defect signatures in this subtype, which were associated with transcriptional downregulation of key DNA repair genes and may revive previously discarded or currently unconsidered therapeutic modalities for genomically stratified melanoma patient subsets. Broadly, harmonized meta-analysis of melanoma whole-exomes identified distinct molecular drivers that may point to multiple opportunities for biological and therapeutic investigation.