Analyses of non-coding somatic drivers in 2,658 cancer whole genomes.

The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available

Table S3 from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Table S3 contains the karyotypes of 16 genome-wide LOH MPM cases from the BWH cohort.</p

Table S2 from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Table S2 contains BAP1 analysis results, as well as detailed lists of YY1 and IRF8 target genes.</p

Supplementary Data from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Supplementary materials and methods, as well as supplementary figures S1-S7.</p

Table S7 from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Table S7 contains microbe screening results.</p

Table S4 from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Table S4 includes immune signature and iCluster results.</p

Table S5 from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Table S5 contains detailed miRs and lncRNAs results.</p

Table S1 from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Table S1 contains cohort description, Master Patient Table and MutSigCV results.</p

Table S6 from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Table S6 contains results from the analysis of DNA methylation in SETD2 mutated and BAP1 inactivated samples.</p

The repertoire of mutational signatures in human cancer

Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature 1. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses 3–15, enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated—but distinct—DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer