Summary Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF-mutant tumors and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.

SUMMARY 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.

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In the originally published version of this paper, there were two instances in which a paper by Raab et al. was cited, but the full reference was accidentally omitted from the reference list. First, in the subsection titled ''Arid1a Haploinsufficiency Alters Global Chromatin Occupancy and Metastasis Genes,'' paragraph 4, the authors wrote, ''To determine if these genes have direct interactions with ARID1A and SWI/SNF components in human HCC, we examined ChIP-seq experiments from HepG2 cells performed by Raab et al.'' Second, in the legend for Figure 7G, the authors wrote, ''ChIP-seq data showing binding of EMILIN1, MAT1A, LCN2, and IL1R1 loci by ARID1A and SNF5 over input in human HepG2 hepatoma cells (data from Raab et al.).''