Search

Many gene fusions are reported in tumours and for most their role remains unknown. As fusions are used for diagnostic and prognostic purposes, and are targets for treatment, it is crucial to assess their function in cancer. To systematically investigate the role of fusions in tumour cell fitness, we utilized RNA-sequencing data from 1011 human cancer cell lines to functionally link 8354 fusion events with genomic data, sensitivity to >350 anti-cancer drugs and CRISPR-Cas9 loss-of-fitness effects. Established clinically-relevant fusions were identified. Overall, detection of functional fusions was rare, including those involving cancer driver genes, suggesting that many fusions are dispensable for tumour fitness. Therapeutically actionable fusions involving RAF1, BRD4 and ROS1 were verified in new histologies. In addition, recurrent YAP1-MAML2 fusions were identified as activators of Hippo-pathway signaling in multiple cancer types. Our approach discriminates functional fusions, identifying new drivers of carcinogenesis and fusions that could have clinical implications., Gene fusions are observed in many cancers but their link to tumour fitness is largely unknown. Here, transcriptomic analysis combined with pharmacological and CRISPR-Cas9 screening of cancer cell lines was used to evaluate the functional linkage between fusions and tumour fitness.

Aims Tricuspid regurgitation (TR) was long forgotten until recent studies alerting on its prognostic impact. Cardiac output (CO) is the main objective of heart mechanics. We sought to compare clinical and echocardiographic data of patients with TR from inclusion to 1-year follow-up according to initial CO. Methods and results Patients with isolated secondary TR and left ventricular ejection fraction (LVEF) ≥40% were prospectively included. All patients had a clinical and echocardiographic evaluation at baseline and after 1 year. Echocardiographic measurements were centralized. The patients were partitioned according to their CO at baseline. The primary outcome was all-cause death. Ninety-five patients completed their follow-up. The majority of patients had normal CO (n = 64, 67.4%), whereas 16 (16.8%) patients had low-CO and 12 (12.6%) had high-CO. right ventricular function was worse in the low-CO group but with improvement at 1 year (30% increase in tricuspid annular plane systolic excursion). LVEF and global longitudinal strain were significantly worse in the low-CO group. Overall, 18 (19%) patients died during follow-up, of which 10 (55%) patients had abnormal CO. There was a U-shaped association between CO and mortality. Normal CO patients had significantly better survival (87.5% vs. 62.5% and 66.67%) in the low- and high-CO groups, respectively, even after adjustment (heart rate 2.23 for the low-CO group and 9.08 for high-CO group; P = 0.0174). Conclusion Significant isolated secondary TR was associated with 19% of mortality. It is also associated with higher long-term mortality if CO is abnormal, suggesting a possible role for evaluating better and selecting patients for intervention.

International audience; LVAD implantation in patients with a recently diagnosed cardiomyopathy has been poorly investigated. This work aims at describing the characteristics and outcomes of patients receiving a LVAD within 30 days following the diagnosis of cardiomyopathy. Patients from the ASSIST-ICD study was divided into recently and remotely diagnosed cardiomyopathy based on the time from initial diagnosis of cardiomyopathy to LVAD implantation using the cut point of 30 days. The primary end point of the study was all-cause mortality at 30-day and during follow-up. A total of 652 patients were included and followed during a median time of 9.1 (2.5 to 22.1) months. In this population, 117 (17.9%) had a recently diagnosed cardiomyopathy and had LVAD implantation after a median time of 15.0 (9.0 to 24.0) days following the diagnosis. This group of patients was significantly younger, with more ischemic cardiomyopathy, more sudden cardiac arrest (SCA) events at the time of the diagnosis and were more likely to receive temporary mechanical support before LVAD compared with the remotely diagnosed group. Postoperative in-hospital survival was similar in groups, but recently diagnosed patients had a better long-term survival after hospital discharge. SCA before LVAD and any cardiac surgery combined with LVAD implantation were identified as 2 independent predictors of postoperative mortality in recently diagnosed patients. In conclusion, rescue LVAD implantation for recently diagnosed severe cardiomyopathy is common in clinical practice. Such patients experience a relatively low postoperative mortality and have a better long-term survival compared with remotely diagnosed patients.

PREMISE OF THE STUDY Leaves of monocots are typically linear with parallel venation, though a few taxa have broad leaves. Studies of stomatal patterning and development in monocots required updating in the context of rapidly improving knowledge of both the phylogenetic and development-genetic context of monocots that facilitate studies of character evolution. METHODS We used an existing microscope-slide collection to obtain data on stomatal structure across all the major monocot clades, including some species with relatively broad leaves. In addition, we used both light and electron microscopy to study stomatal development in 16 selected species. We evaluated these data in a phylogenetic context to assess stomatal character evolution. KEY RESULTS Mature stomatal patterning in monocots can be broadly categorized as anomocytic, paracytic-nonoblique, and paracytic/tetracytic oblique, depending on the presence, development, and arrangement of lateral subsidiary cells. Stomatal meristemoids invariably result from an asymmetric mitosis in monocots. In species where lateral subsidiary cells are present, they are perigene cells. Among monocots with relatively broad leaves, stomatal orientation is linear-axial in most taxa, but transverse in Lapageria and Stemona, and random in Dioscorea and some Araceae. Amplifying divisions are apparently absent in monocots. CONCLUSIONS Anomocytic stomata represent the likely ancestral (plesiomorphic) condition in monocots, though multiple evolutionary transitions and reversals have occurred. Paracytic-nonoblique stomata with highly modified perigene lateral neighbor cells characterize grasses and other Poales. The presence of anomocytic stomata in Japonolirion and Tofieldia reinforces the concept that these two genera have retained many ancestral monocot features and are critical in understanding character evolution in monocots.

Mutations in the ATM tumor suppressor gene confer hypersensitivity to DNA-damaging chemotherapeutic agents. To explore genetic resistance mechanisms, we performed genome-wide CRISPR-Cas9 screens in cells treated with the DNA topoisomerase I inhibitor topotecan. Thus, we here establish that inactivating terminal components of the non-homologous end-joining (NHEJ) machinery or of the BRCA1-A complex specifically confer topotecan resistance to ATM-deficient cells. We show that hypersensitivity of ATM-mutant cells to topotecan or the poly-(ADP-ribose) polymerase (PARP) inhibitor olaparib reflects delayed engagement of homologous recombination at DNA-replication-fork associated single-ended double-strand breaks (DSBs), allowing some to be subject to toxic NHEJ. Preventing DSB ligation by NHEJ, or enhancing homologous recombination by BRCA1-A complex disruption, suppresses this toxicity, highlighting a crucial role for ATM in preventing toxic LIG4-mediated chromosome fusions. Notably, suppressor mutations in ATM-mutant backgrounds are different to those in BRCA1-mutant scenarios, suggesting new opportunities for patient stratification and additional therapeutic vulnerabilities for clinical exploitation., Mutations in the ATM tumor suppressor gene confer hypersensitivity to DNA-damaging chemotherapeutic agents. Here, the authors provide evidence that these hypersensitivities reflect a crucial role for ATM at damaged replication forks being to prevent toxic DNA end-joining leading to chromosome fusions and cell death.

Motivation Large pharmacogenomic screenings integrate heterogeneous cancer genomic datasets as well as anti-cancer drug responses on thousand human cancer cell lines. Mining this data to identify new therapies for cancer sub-populations would benefit from common data structures, modular computational biology tools and user-friendly interfaces. Results We have developed GDSCTools: a software aimed at the identification of clinically relevant genomic markers of drug response. The Genomics of Drug Sensitivity in Cancer (GDSC) database (www.cancerRxgene.org) integrates heterogeneous cancer genomic datasets as well as anti-cancer drug responses on a thousand cancer cell lines. Including statistical tools (analysis of variance) and predictive methods (Elastic Net), as well as common data structures, GDSCTools allows users to reproduce published results from GDSC and to implement new analytical methods. In addition, non-GDSC data resources can also be analysed since drug responses and genomic features can be encoded as CSV files. Supplementary information Supplementary data are available at Bioinformatics online.

Introduction Translating our understanding of genetic alterations in cancer into clinical care remains a major challenge. The discovery of gene fusions such as EML4-ALK in lung cancer and BCR-ABL1 in chronic myeloid leukaemia have already led to changes in clinical care. Advances in next-generation sequencing have accelerated the rate at which novel gene fusions are discovered, but important questions remain about their roles in promoting oncogenic phenotypes and their relevance in drug response. Here, we combine RNA sequencing, CRISPR/Cas9 screens and high-throughput drug sensitivity data in a panel of 1000 human cancer cell lines to examine the occurrence and functional relevance of gene fusions in cancer. Material and methods We performed RNA-sequencing on 1015 human cancer cell lines, representing 42 cancer types. We called fusions using three algorithms: TopHat Fusion, DeFuse and RNA-STAR fusion. Further, we integrate high-throughput drug screening data across >350 compounds, single-nucleotide variants, copy number variation, gene expression data and genome-wide CRISPR/Cas9 dropout screening data to systematically search for gene fusions with functional relevance. Results and discussions We find 8546 distinct gene fusion events across our panel of cell lines. These include well understood gene fusions (e.g. ALK-fusions, BCR-ABL1 and EWSR1-FLI1), as well as novel fusions that involve known cancer driver genes. We are able to recapitulate previously identified gene fusion-drug response associations using an unguided statistical analysis. Furthermore, we developed a systematic unguided approach of using CRISPR/Cas9 gene essentiality data to identify essential gene fusions. This approach recapitulates known essential gene fusions and provides evidence for the oncogenic relevance for previously poorly understood gene fusions. Conclusion In this study, we provide an annotation of gene fusions in 1015 human cancer cell lines. Our systematic analysis of the functional role of gene fusions captures the oncogenic and therapeutic relevance of known gene fusions, and highlights potential therapeutic opportunities of previously uncharacterised gene fusions.