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

Associations between mindfulness, PTSD, and depression in combat deployed post-9/11 military veterans

Objectives: Combat experiences predict PTSD and depression in U.S. military veterans. However, few studies have investigated associations between mindfulness and these constructs. We examined main, direct, and indirect effects for mindfulness and combat experiences on veterans’ PTSD and depressive symptoms and investigated the explanatory value of mindfulness on outcome variance in these models. Methods: A total of 485 post-9/11 era military veterans with previous combat deployments residing in four major US cities completed online surveys asking about their combat experiences, mindfulness, and mental health. Two multivariable ordinary least squares regression models were specified to investigate main effects of mindfulness and combat experiences on veterans’ PTSD and depressive symptoms. Path models examined direct and indirect effects of combat experiences and mindfulness on these outcomes. Results: There were significant associations for mindfulness (β = − 0.68, p < 0.001), (β = − 0.67, p < 0.001) and combat experiences (β = 0.12, p < 0.001), (β = 0.09, p < 0.001) with PTSD and depression respectively. In both models, the addition of the mindfulness parameter significantly increased model R2. Path analysis demonstrated significant direct effects for mindfulness and combat experiences and indirect effects for combat experiences on PTSD and depressive symptoms through the mindfulness pathway. Conclusions: The associations of mindfulness with PTSD and depressive symptoms were greater in magnitude than the associations for combat experiences, and mindfulness explained a large and significant proportion of the variance in outcomes. Additional longitudinal research investigating how mindfulness skills and strategies may buffer against risk for PTSD and depression posed by combat experience is warranted in this high risk population

Promising alternative settings for HPV vaccination of US adolescents

Vaccination in alternative settings, defined here as being outside of traditional primary care, can help address the pressing public health problem of low human papillomavirus vaccine coverage among adolescents in the United States. Pharmacies are promising because they are highly accessible and have well established immunization practices. However, pharmacies currently face policy and reimbursement challenges. School-located mass vaccination programs are also promising because of their high reach and demonstrated success in providing other vaccines, but control by local policymakers and challenges in establishing community partnerships complicate widespread implementation. Health centers in schools are currently too few to greatly increase access to human papillomavirus vaccine. Specialty clinics have experience with vaccination, but the older age of their patient populations limits their reach. Future steps to making alternative settings a success include expanding their use of statewide vaccine registries and improving their coordination with primary care providers