Somatic copy number amplification and gene overexpression are common features of many cancers. To determine the role of gene overexpression on chromosome instability (CIN), we performed genome-wide screens in the budding yeast for yeast genes that cause CIN when overexpressed, a phenotype we refer to as dosage CIN (dCIN), and identified 245 dCIN genes. This catalog of genes reveals human orthologs known to be recurrently overexpressed and/or amplified in tumors. We show that two genes, TDP1, a tyrosyl-DNA-phosphdiesterase, and TAF12, an RNA polymerase II TATA-box binding factor, cause CIN when overexpressed in human cells. Rhabdomyosarcoma lines with elevated human Tdp1 levels also exhibit CIN that can be partially rescued by siRNA-mediated knockdown of TDP1. Overexpression of dCIN genes represents a genetic vulnerability that could be leveraged for selective killing of cancer cells through targeting of an unlinked synthetic dosage lethal (SDL) partner. Using SDL screens in yeast, we identified a set of genes that when deleted specifically kill cells with high levels of Tdp1. One gene was the histone deacetylase RPD3, for which there are known inhibitors. Both HT1080 cells overexpressing hTDP1 and rhabdomyosarcoma cells with elevated levels of hTdp1 were more sensitive to histone deacetylase inhibitors valproic acid (VPA) and trichostatin A (TSA), recapitulating the SDL interaction in human cells and suggesting VPA and TSA as potential therapeutic agents for tumors with elevated levels of hTdp1. The catalog of dCIN genes presented here provides a candidate list to identify genes that cause CIN when overexpressed in cancer, which can then be leveraged through SDL to selectively target tumors.dosage chromosome instability | overexpression | synthetic dosage lethality | TDP1 | rhabdomyosarcoma

Background: Inappropriate prescribing increases patient illness and death owing to adverse drug events. The inclusion of genetic information into primary care medication practices is one solution. Our aim was to assess the ability to obtain and genotype saliva samples and to determine the levels of use of a decision support tool that creates medication options adjusted for patient characteristics, drug-drug interactions and pharmacogenetics. Methods:We conducted a cohort study in 6 primary care settings (5 family practices and 1 pharmacy), enrolling 191 adults with at least 1 of 10 common diseases. Saliva samples were obtained in the physician's office or pharmacy and sent to our laboratory, where DNA was extracted and genotyped and reports were generated. The reports were sent directly to the family physician/pharmacist and linked to an evidence-based prescribing decision support system. The primary outcome was ability to obtain and genotype samples. The secondary outcomes were yield and purity of DNA samples, ability to link results to decision support software and use of the decision support software. Results:Genotyping resulted in linking of 189 patients (99%) with pharmacogenetic reports to the decision support program. A total of 96.8% of samples had at least 1 actionable genotype for medications included in the decision support system. The medication support system was used by the physicians and pharmacists 236 times over 3 months.Interpretation: Physicians and pharmacists can collect saliva samples of sufficient quantity and quality for DNA extraction, purification and genotyping. A clinical decision support system with integrated data from pharmacogenetic tests may enable personalized prescribing within primary care. Trial registration: ClinicalTrials.gov, NCT02383290. AbstractResearch Research CMAJ OPENCMAJ OPEN, 4(3) E529fective at changing prescribing decisions, 13 whereas information given within a physician's workflow has been found to be effective in reducing inappropriate orders for imaging. 14 A medication decision support system (MDSS) is a health information technology system that is designed to provide health care professionals with clinical decision support with medication decision-making tasks. These systems assess whether a drug is safe and effective for the patient, taking into account other medications, diseases and the patient's physical state. 15 We have developed a patient-centred MDSS that assesses the potential drug-drug, drug-condition, druggene and drug-drug-gene interactions and produces a list of drug options least likely to cause harm and most likely to be effective.We conducted a study to assess the DNA collection processes, investigate a panel of pharmacogenetic tests relevant to primary care patients and assess the use of an MDSS. The value of the MDSS will be assessed once feasibility of all processes has been shown. MethodsOver an 18-month period before the start of the trial, we developed a pharmacogenetic panel, a pharmacogenetic report and an MDSS for use in primary...