22 research outputs found
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 survey of natural distribution of yellow tailflower mild mottle virus in south-western Australia reveals new indigenous and exotic hosts
Yellow tailflower mild mottle virus: a new tobamovirus described from Anthocercis littorea (Solanaceae) in Western Australia
Assessing the uniqueness of language: Animal grammatical abilities take center stage
Questions related to the uniqueness of language can only be addressed properly by referring to sound knowledge of the relevant cognitive abilities of nonhuman animals. A key question concerns the nature and extent of animal rule-learning abilities. I discuss two approaches used to assess these abilities. One is comparing the structures of animal vocalizations to linguistic ones, and another is addressing the grammatical rule- and pattern-learning abilities of animals through experiments using artificial grammars. Neither of these approaches has so far provided unambiguous evidence of advanced animal abilities. However, when we consider how animal vocalizations are analyzed, the types of stimuli and tasks that are used in artificial grammar learning experiments, the limited number of species examined, and the groups to which these belong, I argue that the currently available evidence is insufficient to arrive at firm conclusions concerning the limitations of animal grammatical abilities. As a consequence, the gap between human linguistic rule-learning abilities and those of nonhuman animals may be smaller and less clear than is currently assumed. This means that it is still an open question whether a difference in the rule-learning and rule abstraction abilities between animals and humans played the key role in the evolution of language
Recurrent somatic mutations reveal new insights into consequences of mutagenic processes in cancer
The sheer size of the human genome makes it improbable that identical somatic mutations at the exact same position are observed in multiple tumours solely by chance. The scarcity of cancer driver mutations also precludes positive selection as the sole explanation. Therefore, recurrent mutations may be highly informative of characteristics of mutational processes. To explore the potential, we use recurrence as a starting point to cluster >2,500 whole genomes of a pan-cancer cohort. We describe each genome with 13 recurrence-based and 29 general mutational features. Using principal component analysis we reduce the dimensionality and create independent features. We apply hierarchical clustering to the first 18 principal components followed by k-means clustering. We show that the resulting 16 clusters capture clinically relevant cancer phenotypes. High levels of recurrent substitutions separate the clusters that we link to UV-light exposure and deregulated activity of POLE from the one representing defective mismatch repair, which shows high levels of recurrent insertions/deletions. Recurrence of both mutation types characterizes cancer genomes with somatic hypermutation of immunoglobulin genes and the cluster of genomes exposed to gastric acid. Low levels of recurrence are observed for the cluster where tobacco-smoke exposure induces mutagenesis and the one linked to increased activity of cytidine deaminases. Notably, the majority of substitutions are recurrent in a single tumour type, while recurrent insertions/deletions point to shared processes between tumour types. Recurrence also reveals susceptible sequence motifs, including TT[C>A]TTT and AAC[T>G]T for the POLE and 'gastric-acid exposure' clusters, respectively. Moreover, we refine knowledge of mutagenesis, including increased C/G deletion levels in general for lung tumours and specifically in midsize homopolymer sequence contexts for microsatellite instable tumours. Our findings are an important step towards the development of a generic cancer diagnostic test for clinical practice based on whole-genome sequencing that could replace multiple diagnostics currently in use.We acknowledge the support of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) through the Instituto de Salud Carlos III and the 2014-2020 Smart Growth Operating Program, to the EMBL partnership and co-financing with the European Regional Development Fund (MINECO/FEDER, BIO2015-71792-P - awarded to IGG). We also acknowledge the support of the Centro de Excelencia Severo Ochoa, and the Generalitat de Catalunya through the Departament de Salut, Departament d’Empresa i Coneixement and the CERCA Programme. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript