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

Extraction, entanglements, and (im)materialities: Reflections on the methods and methodologies of natural resource industries fieldwork

This multi-authored collection of papers examines the complex realities of research on natural resource industries, including the messy entanglements of extraction, materiality, and everyday social life this research entails. Of central importance to the contributors is how scholars confront fieldwork challenges ethically, methodologically, and corporeally. The collection has two key objectives. First, it expands our understanding of extractive industry by bringing together work on resources conventionally understood as extractive (e.g. oil and minerals) alongside resource-intensive industries not typically examined through an extractive lens, for instance fisheries, agricultural monocultures, water, and tourism. As such, it considers the historical and current conditions that facilitate the extraction of resources in parallel, cyclical, and reproducing forms. Second, the collection examines scholarly positionalities, methodologies, and dilemmas that arise when studying nature-intensive industries, including the extractive dimensions associated with social research itself. Together, the pieces argue that research concerning extractive industries entails multiple scholarly positions—positions problematically inflected with colonialism and always shaped by power relations. Contributors to the section draw largely from feminist, postcolonial, anti-racist, and historical materialist insights to frame and problematize the corporeal and representational concerns arising from their scholarship on nature-intensive industries, including personal dilemmas that they have encountered in their work. Overall, the collection is driven by the realization that research, and the analyses it entails, may serve as a tool for emancipatory intervention yet also reproduce inequality. The futures of the people and ecosystems at the center of our studies impel constant reflection so that our work, and that of the next generation of scholars, may offer critical analysis that contributes to transforming—rather than reinforcing—oppressive relations associated with extractive sectors and industries