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

The effectiveness of home versus community-based weight control programmes initiated soon after breast cancer diagnosis: a randomised controlled trial

BackgroundBreast cancer diagnosis may be a teachable moment for lifestyle behaviour change and to prevent adjuvant therapy associated weight gain. We assessed the acceptability and effectiveness of two weight control programmes initiated soon after breast cancer diagnosis to reduce weight amongst overweight or obese women and prevent gains in normal-weight women.MethodsOverweight or obese (n?=?243) and normal weight (n?=?166) women were randomised to a three-month unsupervised home (home), a supervised community weight control programme (community) or to standard written advice (control). Primary end points were change in weight and body fat at 12 months. Secondary end points included change in insulin, cardiovascular risk markers, quality of life and cost-effectiveness of the programmes.ResultsForty-three percent of eligible women were recruited. Both programmes reduced weight and body fat: home vs. control mean (95% CI); weight ?2.3 (?3.5, ?1.0) kg, body fat ?1.6 (?2.6, ?0.7) kg, community vs. control; weight ?2.4 (?3.6, ?1.1) kg, body fat ?1.4 (?2.4, ?0.5) kg (all p?<?0.001). The community group increased physical activity, reduced insulin, cardiovascular disease risk markers, increased QOL and was cost-effective.ConclusionsThe programmes were equally effective for weight control, but the community programme had additional benefits.Clinical trial registrationISRCTN6857614

The management of strategic-foresight activities : evidence from large european multinationals

Despite the strategic relevance of strategic-foresight activities, the strategic-management literature contains only little and fragmented knowledge of how firms successfully manage such activities. This exploratory paper provides insights into the management of strategic-foresight activities based on in-depth case studies of five large multinational companies. According to our findings, strategic-foresight activities (1) are structurally managed within an organization via one of three models, (2) consist of initiation, modeling, and finalization phases, which occur in circular, iterative loops, (3) use increasingly qualitative and participative methods, (4) support strategic decision-making with a main focus either on innovation and exploration or on planning and exploitation, (5) are subject to substantial change depending on the content-related openness of the corporate strategy (diversification vs. focusing) and the openness of the strategic-planning process (outside vs. inside orientation), and (6) are induced by a radical and sudden change in the corporate strategy