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

A stochastic optimization model for supporting urban drainage design under complexity

A stochastic optimization model for urban drainage design (SODD) was proposed in this study to help analyze the tradeoff between investment and acceptable flood damage in urban drainage designs considering effects of both uncertainty and climate change. The simulation model (i.e. SWMM), driven by designed rainfall either from existing Intensity-Duration-Frequency (IDF) curves or future ones subjected to climate change conditions, was used to simulate flooding scenarios. The generalized uncertainty analysis estimation (GLUE) and Monte Carlo simulation methods were employed to quantify the system reliability which was adopted in the constraints of the optimization model. The results from a case study showed that the deterministic optimization was computationally efficient with no randomness encountered in hydrological simulation, although its solution was hardly reliable in achieving the target for flood mitigation. The stochastic version, on the other hand, could offer richer information on system reliability and help managers make a more robust decision. The results also revealed that the rainfall extremes under the impact of climate change could significantly affect system investment. The proposed method is advantageous in facilitating cost-effective planning towards a risk-based drainage design in light of various complexities

Morphological evolution of a barchan dune migrating past an offshore wind farm foundation

As the number of manmade structures installed on the seafloor is increasing rapidly, we seek to understand the impact of these immobile obstacles on marine geomorphological processes, such as the evolution of bedforms. A 5.8 m diameter monopile foundation was installed at the case study offshore windfarm approximately 30 m ahead of an approaching barchan (crescent‐shaped) dune. The impact of the monopile on the dune's evolution was analysed using six multibeam bathymetry surveys spanning 20 years. To substantiate this analysis, coupled three‐dimensional numerical modelling of flows and sediment was conducted in which the scour inducing bed shear stresses were calculated from the modelled turbulent kinetic energy. Following the installation of the monopile, the mid‐section of the dune accelerated and stretched in the direction of the wake of the monopile. Four years after the monopile's installation the rest of the dune had caught up, flattening out the slip face within half the dune's length downstream of the monopile. Due to the modified flow field, the dune was scoured deeply at the base of the monopile to a depth of 6.8 m (supported by the model results that predicted a scour depth exceeding 2 m over a period of just a few days). The surveyed volume of material scoured amounted to 8% of the total dune volume. Whilst the process of scouring occurs at a timescale of days to weeks, the dune migrated on average by 25 m/yr. The difference in the timescale of the two processes allowed the scouring to occur through the full thickness of the dune. The scoured dune profile recovered rapidly once the dune migrated downstream of the monopile. This article demonstrates how large geomorphological features can intercept and migrate past a monopile foundation without long‐lasting impacts on the integrity of the feature or the foundation