The functional impact of the vast majority of cancer somatic mutations remains unknown, representing a critical knowledge gap for implementing precision oncology. Here, we report the development of a moderate-throughput functional genomic platform consisting of efficient mutant generation, sensitive viability assays using two growth factor-dependent cell models, and functional proteomic profiling of signaling effects for select aberrations. We apply the platform to annotate >1,000 genomic aberrations, including gene amplifications, point mutations, indels, and gene fusions, potentially doubling the number of driver mutations characterized in clinically actionable genes. Further, the platform is sufficiently sensitive to identify weak drivers. Our data are accessible through a user-friendly, public data portal. Our study will facilitate biomarker discovery, prediction algorithm improvement, and drug development.

There is a lack of consensus on the diagnosis and management of patients with brief runs of atrial arrhythmia detected on ambulatory ECG. Further research is needed to clarify the risk of stroke in this unique population of patients.

A recording of ≥ 30 seconds is required to diagnose paroxysmal atrial fibrillation when using ambulatory ECG monitoring. It is unclear if shorter runs are relevant with regards to stroke risk. Methods An online survey of cardiologists and stroke physicians was carried out to assess current management of patients with short runs of atrial arrhythmia within Europe. Results Respondents included 311 clinicians from 32 countries. To diagnose atrial fibrillation, 80% accepted a single 12-lead ECG and 36% accepted a single run of < 30 seconds on ambulatory monitoring. Stroke physicians were twice as likely to accept < 30 seconds of arrhythmia as being diagnostic of atrial fibrillation (OR 2.43, 95% CI 1.19-4.98). They were also more likely to advocate anticoagulation for hypothetical patients with lower risk; OR 1.9 (95% CI 1.0-3.5) for a patient with CHA2DS2-VASc = 2. Conclusion Short runs of atrial fibrillation create a dilemma for physicians across Europe. Stroke physicians and cardiologists differ in their diagnosis and management of these patients. KeywORDS atrial arrhythmia, detection, online survey, strokeDeClARATION Of INTeReSTS KRL is chairman of the independent data monitoring committee for the ESUS-RESPECT trial sponsored by Boehringer Ingelheim, and has received grant support for research into post-stroke AF detection from the Chief Scientist Office for Scotland. MeTHODS Survey questionnaireA survey questionnaire was created using Survey Monkey (www.surveymonkey.com). This comprised 12 questions: three to define basic demographic data for respondents; four to determine each respondent's diagnostic criteria for AF; two to establish their current practice regarding the investigation of possible AF following ischaemic stroke; and three to investigate specific factors that would influence a physician's decision to start oral anticoagulant treatment (Appendix 1, available with the online version of this paper). All questions required an answer to complete the survey, with space for optional additional comments at the end. The aim was not to assess physicians' knowledge of clinical guidelines, but rather to elicit what clinicians do in their daily practice. For the purposes of the survey, electrocardiographic findings suggestive of AF were defined as 'atrial arrhythmia without p waves and with irregular ventricular response'.The online survey was opened on 3 December 2014 and a link to the survey was emailed to national and European societies for cardiology and stroke medicine, along with a cover letter providing additional information. The survey link was included in the electronic newsletters of the European Society of Cardiology, the European Stroke Organisation and the AF Association. In order to maximise the response rate, national cardiac and stroke societies affiliated with the above European organisations were emailed directly (59 and 31 societies, respectively). A reminder email was sent in March 2015. Positive responses were received from the following national societies confirming the distrib...

Fusion genes represent a class of attractive therapeutic targets. Thousands of fusion genes have been identified in patients with cancer, but the functional consequences and therapeutic implications of most of these remain largely unknown. Here, we develop a functional genomic approach that consists of efficient fusion reconstruction and sensitive cell viability and drug response assays. Applying this approach, we characterize ~100 fusion genes detected in patient samples of The Cancer Genome Atlas, revealing a notable fraction of low-frequency fusions with activating effects on tumor growth. Focusing on those in the RTK-RAS pathway, we identify a number of activating fusions that can markedly affect sensitivity to relevant drugs. Last, we propose an integrated, level-of-evidence classification system to prioritize gene fusions systematically. Our study reiterates the urgent clinical need to incorporate similar functional genomic approaches to characterize gene fusions, thereby maximizing the utility of gene fusions for precision oncology.