Integrated molecular drivers coordinate biological and clinical states in melanoma

• Published in: Nature genetics Vol. 52; no. 12; pp. 1373 - 1383
• Main Authors: Conway, Jake R, Dietlein, Felix, Taylor-Weiner, Amaro, AlDubayan, Saud, Vokes, Natalie, Keenan, Tanya, Reardon, Brendan, He, Meng Xiao, Margolis, Claire A, Weirather, Jason L, Haq, Rizwan, Schilling, Bastian, Stephen Hodi, F, Schadendorf, Dirk, Liu, David, Van Allen, Eliezer M
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.12.2020
• Subjects: Cancer; Care and treatment; Cellular signal transduction; Deoxyribonucleic acid; Development and progression; DNA; DNA repair; DNA Repair - genetics; DNA Repair-Deficiency Disorders - genetics; Gene mutations; Genes; Genetic aspects; Genetic Predisposition to Disease - genetics; Genomics; Growth factors; GTP Phosphohydrolases - genetics; Health aspects; Humans; Immune checkpoint; Immunotherapy; Inactivation; Kinases; Melanoma; Melanoma - genetics; Melanoma - pathology; Membrane Proteins - genetics; Mutation; Neurofibromin 1 - genetics; Patients; Proto-Oncogene Proteins B-raf - genetics; Repair; Signal Transduction - genetics; Skin Neoplasms - genetics; Skin Neoplasms - pathology; SWI/SNF complex; Transcription; Transforming growth factors; Tumors; Whole Exome Sequencing; United States
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-020-00739-1

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 (TWT)), 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 transforming growth factor-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 TWT melanomas and revealed 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 revealed distinct molecular drivers that may point to multiple opportunities for biological and therapeutic investigation.