Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

The overlooked role of physical activity in mitigating the mortality risk in smokers and nonsmokers with COPD

Background Chronic obstructive pulmonary diseases (COPD), found in smokers and nonsmokers, are known to have increased mortality, but most people with COPD are unaware of their condition. They have a reduced exercise capacity and in general are less physically active, even though long-term benefits of physical activity have been demonstrated. Methods A total of 386,304 people participated in a health surveillance program between 1994 and 2008 in Taiwan. Lung function, blood tests, and medical history data, including smoking and exercise habits, were collected. Corresponding mortality and cancer data were retrieved from the National Death File and the National Cancer Registry, respectively. COPD was diagnosed by spirometry, as recommended by GOLD standard Results In a mean of 8.8-year follow-up, the prevalence of smokers and non-smokers with COPD was 5.3% and 3.7% respectively. Using Cox proportional hazard regression with factor adjustment, hazard ratio (HR) were 1.56 (1.46-1.66) in smoker, 1.48 (1.36-1.62) in those with COPD and 2.14 (1.97-2.34) in smokers with COPD. In those with COPD, fully active LTPA (>30 min/day), regardless of history of smoking, can reduce the all-cause mortality compared with inactive LTPA (< 15min/day). For all-cause mortality in those without COPD or cardiovascular disease-related mortality in those with COPD, low active LTPA (15-30 min/day) can decrease the HR compared with the corresponding group. The active LTPA may extend the estimated life expectancy about 3 years in participants with COPD. Conclusions COPD is a systemic disease, causing non-lung related excess mortality such as CVD and cancer, and shortening life by 6 years. These excesses could be substantially mitigated by regular physical activity for 30 or more minutes/day of moderate intensity

Smokers with a high normal heart rate (80-99/min) found their life span shortened by 13 years

Background Not all smokers are alike in their mortality risk. Heart rate is not routinely considered as a CVD or mortality risk when the rate is less than 100/min, and both smokers and doctors are unaware of any risk from normal heart rate. Methods The cohort, 434,496, was recruited from participants in a health surveillance program between 1994 and 2008. Mortality was followed up by matching with National Death file. Resting heart rate was measured by EKG. Hazard ratios (HR) and life expectancy were calculated, based on the reference group of those with heart rates 60-69/min. Results Smoking prevalence among male was 40.6% with 85,996 smokers in the cohort. Mortality risks increased incrementally with increasing heart rate from 70-79, 80-89, to ≥90. HR with high normal heart rate, 80-99/min, was 1.60 compared to smoker with 60-69/min and 2.69 compared to nonsmoker with 60-69/min. Heart Rate N(%) Deaths HR (95% CI) Life expectancy at age 30 Life expectancy difference from 60-69 60-69 29,735 (34.6%) 889 1 (Reference) 54.27 (Reference) ≥ 90 4,110 (4.8%) 419 2.53 (2.25-2.84)* 42.57 11.70 80-99 (Compared with smokers with heart rate 60-69) 15,785 (18.4%) 969 1.60 (1.46-1.76)* 48.03 6.24 80-99 (Compared with nonsmokers with heart rate 60-69) 15,785 (8.4%) 969 2.69 (2.42-2.99)* 48.03 13.42 [Mortality and life expectancy for smoker] Conclusions Smokers with high normal heart rate, constituted nearly one fifth of smoking population, shortened life by 13 years compared to nonsmokers. Two out of three smokers in this group were expected to die from smoking related causes. Finding rapid heart rate among smokers could be used to further motivate smokers to quit, by sharing its high mortality risk