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

Process evaluation of the Albany Physical Activity and Nutrition (APAN) program, a home-based intervention for metabolic syndrome and associated chronic disease risk in rural Australian adults

Issue addressed: The Albany Physical Activity and Nutrition (APAN) study investigated the effects of the APAN program, a home-based intervention on dietary and physical activity behaviours and chronic disease risk for rural Australian adults. This paper reports on the process evaluation to gain insight into the link between intervention elements and outcomes. Methods: The APAN program comprised resources to improve participants' diet and physical activity. Printed and online resources were provided to participants, complemented by motivational interviews via telephone. Process evaluation used mixed-methods, with a sample of 201 intervention participants residing in a disadvantaged rural area. Participants were aged 50 to 69 years with, or at risk of, metabolic syndrome. Quantitative data were collected using an online survey (n = 73); qualitative data were collected via telephone exit interviews with intervention completers (n = 8) and non-completers (n = 8), and recruitment notes recorded by research assistants. Results: The attrition rate of the program was 18%; major reasons for withdrawal were health and personal issues and a loss of interest. The majority of participants found the printed resources useful, attractive, and suitable to their age group. The website was the least preferred resource. Reasons for completing the program included the desired health benefits, wanting to honour the commitment, and wanting to assist with research. Conclusions: Carefully planned recruitment will reduce the burden on resources and improve uptake. Understanding reasons for attrition such as family or personal barriers and health issues will assist practitioners to support participants overcome these barriers. Given participants' preference for printed resources, and the known effectiveness of these in combination with other strategies, investigating methods to encourage use of telephone and online support should be a priority. So what?: This process evaluation provided an overview of recruitment challenges and preferred intervention components. It is desirable that future work determines the most effective intervention components for rural adults at risk of chronic disease.</p

Long-term sustainability of a physical activity and nutrition intervention for rural adults with or at risk of metabolic syndrome

Objective: To determine longer-term (18-month) sustainability of a six-month physical activity and nutrition intervention for 50-69-year-olds with or at risk of metabolic syndrome residing in a rural Australian community. Methods: Participants (n=151) were followed-up at 12 and 18 months post-intervention. Changes in nutrition behaviours (fat and fibre barometer); physical activity behaviours (IPAQ); anthropometry (waist-hip ratio, weight, BMI), blood pressure, blood parameters (triglycerides, glucose, LDL-, HDL-, non-HDL, total-cholesterol) were analysed using t-tests and repeated measures ANOVA. Results: Across three time points (6, 12 and 18 months) marginal decrease was observed for waist circumference (p=0.001), a modest increase was observed for diastolic blood pressure (p=0.010) and other outcome measures remained stable. Conclusion: Maintenance and ongoing improvement of health behaviours in the longer-term is challenging. Future studies must look for ways to embed interventions into communities so they are sustainable and investigate new approaches to reduce the risk of chronic disease. Implications for public health: Metabolic syndrome is a major health issue in Australia and worldwide. Early identification and management are required to prevent the progression to chronic disease. This 18-month follow-up showed that outcomes measures remained relatively stable; however, there is a need to investigate opportunities for embedded community interventions to support long-term health behaviour change.</p