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

General practitioners’ views on (long-term) prescription and use of problematic and potentially inappropriate medication for oldest-old patients—A qualitative interview study with GPs (CIM-TRIAD study)

Background: Potentially inappropriate medication (PIM) is defined as medication with uncertain therapeutic effects and/ or potential adverse drug reactions outweighing the clinical benefits. The prescription rate of PIM for oldest- old patients is high despite the existence of lists of PIM (e. g. the PRISCUS list) and efforts to raise awareness. This study aims at identifying general practitioners' views on PIM and aspects affecting the (long- term) use of PIM. Methods: As part of the CIM- TRIAD study, we conducted semi- structured, qualitative interviews with 47 general practitioners, discussing 25 patients with and 22 without PIM (according to the PRISCUS list). The interview guideline included generic and patient- specific questions. Interviews were digitally recorded and transcribed verbatim. We content analyzed the interviews using deductive and inductive category development. Results: The majority of the general practitioners were not aware of the PRISCUS list. Agents deemed potentially inappropriate from the general practitioners' point of view and the PRISCUS list are not completely superimposable. General practitioners named their criteria to identify appropriate medication for elderly patients (e. g. renal function, cognitive state) and emphasized the importance of monitoring. We identified prescription- (e. g. benzodiazepines on alternative private prescription), medication- (e. g. subjective perception that PIM has no alternative), general practitioner- (e. g. general practitioner relies on specialists), patient( e. g. demanding high- user, positive subjective benefit- risk- ratio) and system- related aspects (e. g. specialists lacking holistic view, interface problems) related to the (long term) use of PIM. Conclusions: While the PRISCUS list does not seem to play a decisive role in general practice, general practitioners are well aware of risks associated with PIM. Our study identifies some starting points for a safer handling of PIM, e. g. stronger dissemination of the PRISCUS list, better compensation of medication reviews, positive lists, adequate patient information, multifaceted interventions and improved communication between general practitioners and specialists