Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Comprehensive molecular characterization of the hippo signaling pathway in cancer

Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional “omic” data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era

The predictability of near-coastal currents using a baroclinic unstructured grid model

A limited domain, coastal ocean forecast system consisting of an unstructured grid model, a meteorological model, a regional ocean model, and a global tidal database is designed to be globally relocatable. For such a system to be viable, the predictability of coastal currents must be well understood with error sources clearly identified. To this end, the coastal forecast system is applied at the mouth of Chesapeake Bay in response to a Navy exercise. Two-day forecasts are produced for a 10-day period from 4 to 14 June 2010 and compared to real-time observations. Interplay between the temporal frequency of the regional model boundary forcing and the application of external tides to the coastal model impacts the tidal characteristics of the coastal current, even contributing a small phase error. Frequencies of at least 3 h are needed to resolve the tidal signal within the regional model; otherwise, externally applied tides from a database are needed to capture the tidal variability. Spatial resolution of the regional model (3 vs 1 km) does not impact skill of the current prediction. Tidal response of the system indicates excellent representation of the dominant M2 tide for water level and currents. Diurnal tides, especially K1, are amplified unrealistically with the application of coarse 27-km winds. Higher-resolution winds reduce current forecast error with the exception of wind originating from the SSW, SSE, and E. These winds run shore parallel and are subject to strong interaction with the shoreline that is poorly represented even by the 3-km wind fields. The vertical distribution of currents is also well predicted by the coastal model. Spatial and temporal resolution of the wind forcing including areas close to the shoreline is the most critical component for accurate current forecasts. Additionally, it is demonstrated that wind resolution plays a large role in establishing realistic thermal and density structures in upwelling prone regions