Biomarkers, Tumor; DNA Copy Number Variations; DNA Methylation; Eukaryotic Initiation Factor-1; Gene Expression Regulation, Neoplastic; Humans; Melanoma; Monosomy; Mutation; Phosphoproteins; Prognosis; RNA Splicing Factors; Serine-Arginine Splicing Factors; Tumor Suppressor Proteins; Ubiquitin Thiolesterase; Uveal Neoplasms
Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes.
Institute for Systems Biology
Robertson, A Gordon; Shih, Juliann; Yau, Christina; Gibb, Ewan A; Oba, Junna; Mungall, Karen L; Hess, Julian M; Uzunangelov, Vladislav; Walter, Vonn; Danilova, Ludmila; Lichtenberg, Tara M; Kucherlapati, Melanie; Kimes, Patrick K; Tang, Ming; Penson, Alexander; Babur, Ozgun; Akbani, Rehan; Bristow, Christopher A; Hoadley, Katherine A; Iype, Lisa; Chang, Matthew T; Cherniack, Andrew D; Benz, Christopher; Mills, Gordon B; Verhaak, Roel G W; Griewank, Klaus G; Felau, Ina; Zenklusen, Jean C; Gershenwald, Jeffrey E; Schoenfield, Lynn; Lazar, Alexander J; Abdel-Rahman, Mohamed H; Roman-Roman, Sergio; Stern, Marc-Henri; Cebulla, Colleen M; Williams, Michelle D; Jager, Martine J; Coupland, Sarah E; Esmaeli, Bita; Kandoth, Cyriac; and Woodman, Scott E, "Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma." (2017). Articles, Abstracts, and Reports. 2327.