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

Sediment flux driven channel geometry adjustment of bedrock and mixed gravel‐bedrock rivers

International audienceSediment supply (Qs) is often overlooked in modelling studies of landscape evolution, despite sediment playing a key role in the physical processes that drive erosion and sedimentation in river channels. Here, we show the direct impact of the supply of coarse‐grained, hard, sediment on the geometry of bedrock channels from the Rangitikei river, New Zealand. Channels receiving a coarse bedload sediment supply are systematically (up to an order of magnitude) wider than channels with no bedload sediment input for a given discharge. We also present physical model experiments of a bedrock river channel with a fixed water discharge (1.5 l/min) under different Qs (between 0 and 20 g/l) that allow the quantification of the role of sediment in setting the width and slope of channels and the distribution of shear stress within channels. The addition of bedload sediment increases the width, slope, and width‐to‐depth ratio of the channels, and increasing sediment loads promote emerging complexity in channel morphology and shear stress distributions. Channels with low Qs are characterised by simple in‐channel morphologies with a uniform distribution of shear stress within the channel while channels with high Qs are characterised by dynamic channels with multiple active threads and a non‐uniform distribution of shear stress. We compare bedrock channel geometries from the Rangitikei and the experiments to alluvial channels and demonstrate that the behaviour is similar, with a transition from single thread and uniform channels to multiple threads occurring when bedload sediment is present. In the experimental bedrock channels, this threshold Qs is when the input sediment supply exceeds the transport capacity of the channel. Caution is required when using the channel geometry to reconstruct past environmental conditions or to invert for tectonic uplift rates, because multiple configurations of channel geometry can exist for a given discharge, solely due to input Qs