ERBB family fusions are recurrent and actionable oncogenic targets across cancer types

PurposeGene fusions involving receptor tyrosine kinases (RTKs) define an important class of genomic alterations with many successful targeted therapies now approved for ALK, ROS1, RET and NTRK gene fusions. Fusions involving the ERBB family of RTKs have been sporadically reported, but their frequency has not yet been comprehensively analyzed and functional characterization is lacking on many types of ERBB fusions.Materials and methodsWe analyzed tumor samples submitted to Caris Life Sciences (n=64,354), as well as the TCGA (n=10,967), MSK IMPACT (n=10,945) and AACR GENIE (n=96,324) databases for evidence of EGFR, ERBB2 and ERBB4 gene fusions. We also expressed several novel fusions in cancer cell lines and analyzed their response to EGFR and HER2 tyrosine kinase inhibitors (TKIs).ResultsIn total, we identified 1,251 ERBB family fusions, representing an incidence of approximately 0.7% across all cancer types. EGFR, ERBB2, and ERBB4 fusions were most frequently found in glioblastoma, breast cancer and ovarian cancer, respectively. We modeled two novel types of EGFR and ERBB2 fusions, one with a tethered kinase domain and the other with a tethered adapter protein. Specifically, we expressed EGFR-ERBB4, EGFR-SHC1, ERBB2-GRB7 and ERBB2-SHC1, in cancer cell lines and demonstrated that they are oncogenic, regulate downstream signaling and are sensitive to small molecule inhibition with EGFR and HER2 TKIs.ConclusionsWe found that ERBB fusions are recurrent mutations that occur across multiple cancer types. We also establish that adapter-tethered and kinase-tethered fusions are oncogenic and can be inhibited with EGFR or HER2 inhibitors. We further propose a nomenclature system to categorize these fusions into several functional classes

Human plague: An old scourge that needs new answers

Yersinia pestis, the bacterial causative agent of plague, remains an important threat to human health. Plague is a rodent-borne disease that has historically shown an outstanding ability to colonize and persist across different species, habitats, and environments while provoking sporadic cases, outbreaks, and deadly global epidemics among humans. Between September and November 2017, an outbreak of urban pneumonic plague was declared in Madagascar, which refocused the attention of the scientific community on this ancient human scourge. Given recent trends and plague’s resilience to control in the wild, its high fatality rate in humans without early treatment, and its capacity to disrupt social and healthcare systems, human plague should be considered as a neglected threat. A workshop was held in Paris in July 2018 to review current knowledge about plague and to identify the scientific research priorities to eradicate plague as a human threat. It was concluded that an urgent commitment is needed to develop and fund a strong research agenda aiming to fill the current knowledge gaps structured around 4 main axes: (i) an improved understanding of the ecological interactions among the reservoir, vector, pathogen, and environment; (ii) human and societal responses; (iii) improved diagnostic tools and case management; and (iv) vaccine development. These axes should be cross-cutting, translational, and focused on delivering context-specific strategies. Results of this research should feed a global control and prevention strategy within a “One Health” approach

Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma

SummaryWe describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers

Omics-based molecular techniques in oral pathology centred cancer: Prospect and challenges in Africa

: The completion of the human genome project and the accomplished milestones in the human proteome project; as well as the progress made so far in computational bioinformatics and “big data” processing have contributed immensely to individualized/personalized medicine in the developed world.At the dawn of precision medicine, various omics-based therapies and bioengineering can now be applied accurately for the diagnosis, prognosis, treatment, and risk stratifcation of cancer in a manner that was hitherto not thought possible. The widespread introduction of genomics and other omics-based approaches into the postgraduate training curriculum of diverse medical and dental specialties, including pathology has improved the profciency of practitioners in the use of novel molecular signatures in patient management. In addition, intricate details about disease disparity among diferent human populations are beginning to emerge. This would facilitate the use of tailor-made novel theranostic methods based on emerging molecular evidences

Chapter 10. Live vaccines against plague and pseudotuberculosis

International audienceThe reemergence of plague in the world, the appearance of antibiotic-resistant strains and the risk that genetically modified Y. pestis could serve as a bioterrorist weapon have fostered a renewed interest for vaccination. Currently, researchers mainly follow two distinct vaccinal strategies: one is the development of acellular sub-unit vaccines based on two recombinant targets (F1 and V), and the other is the development of improved live vaccines. Live plague vaccines have been previously largely used in humans and their efficiency against bubonic plague is not disputed. Rather, critics pointed to a limited duration of protection, an unverified protection against pneumonic plague, instability of vaccine seed strain characteristics and the fact that vaccination could induce severe local and systemic reactions. New live vaccine candidates should combine both the known advantages of replicating vaccines: humoral and cell-mediated immune responses, robustness against mutant microorganisms, easiness of mass production and use, limited cost, etc. whilst providing guarantees in terms of security, stability and efficiency against pneumonic plague. They are based not only on attenuated Y. pestis strains, but also on other Yersiniae and live vectors (Salmonella, viruses) expressing Y. pestis antigens. Vaccines against enteropathogenic Yersiniae are also developed

Oral vaccination against plague using Yersinia pseudotuberculosis

International audienceYersinia pestis, the agent of plague, is among the deadliest bacterial pathogens affecting humans, and is a potential biological weapon. Because antibiotic resistant strains of Yersinia pestis have been observed or could be engineered for evil use, vaccination against plague might become the only means to reduce mortality. Although plague is re-emerging in many countries, a vaccine with worldwide license is currently lacking. The vaccine strategy described here is based on an oral vaccination with an attenuated strain of Yersinia pseudotuberculosis. Indeed, this species is genetically almost identical to Y. pestis, but has a much lower pathogenicity and a higher genomic stability. Gradual modifications of the wild-type Yersinia pseudotuberculosis strain IP32953 were performed to generate a safe and immunogenic vaccine. Genes coding for three essential virulence factors were deleted from this strain. To increase cross-species immunogenicity, an F1-encapsulated Y. pseudotuberculosis strain was then generated. For this, the Y. pestis caf operon, which encodes F1, was inserted first on a plasmid, and subsequently into the chromosome. The successive steps achieved to reach maximal vaccine potential are described, and how each step affected bacterial virulence and the development of a protective immune response is discussed. The final version of the vaccine, named VTnF1, provides a highly efficient and long-lasting protection against both bubonic and pneumonic plague after a single oral vaccine dose. Since a Y. pestis strain deprived of F1 exist or could be engineered, we also analyzed the protection conferred by the vaccine against such strain and found that it also confers full protection against the two forms of plague. Thus, the properties of VTnF1 makes it one of the most efficient candidate vaccine for mass vaccination in tropical endemic areas as well as for populations exposed to bioterrorism

Sélection génétique par les pandémies de peste

Revue pédagogique à l'intention des enseignants en sciences du second degré, aux scientifiques du domaine et plus largement aux lecteurs intéressés.DoctoralLiving organisms best fitted to survive and reproduce are the winners of the natural selection process. Infectious diseases are thought to exert a strong selection pressure on the immune system, thus contributing to eliminate deleterious genes and to positively select genetic variants providing a survival advantage. Because of the enormous death toll payed by mankind to historical plague pandemics, the highly pathogenic bacteria Yersinia pestis probably favored the selection of such genetic variants among survivors. Methods to evidence these effects have considerably evolved in the last decades with the onset of mass genome sequencing and exploding computation capacities, favoring the development of population genetics approaches such as genome-wide association studies (GWAS) over a priori candidate-gene approaches. In this review, early and recent studies and hypotheses on natural selection by plague are gathered and the related immune mechanisms described, when available. Several genes which may have been selected by plague are associated with susceptibility to inflammatory or autoimmune diseases, highlighting the impact of mutations affecting immunity-related genes. Finally, how effects of natural selection on the pathogen itself and its animal hosts mirrors those in man is proposed.Les organismes vivants les mieux adaptés à survivre et se reproduire sont les grands gagnants du processus de sélection naturelle. Les maladies infectieuses exercent une forte pression de sélection sur le système immunitaire, contribuant à éliminer des allèles délétères et à sélectionner positivement les variants amenant un avantage en termes de survie. Du fait que l’humanité a payé un tribut énorme à la peste en nombre de morts durant les pandémies historiques, la bactérie Yersinia pestis, hautement pathogène, a probablement favorisé la sélection de tels variants génétiques chez les survivants. Les méthodes pour analyser ces effets ont considérablement évolué durant les dernières décennies avec l’arrivée du séquençage de génome à haut débit, et l’explosion de la puissance de calcul des ordinateurs, amenant les approches de génétique des populations telles que les études d’association pangénomiques à prendre le pas sur les approches ciblées sur des gènes candidats déterminés a priori. Dans cette revue, les études anciennes et récentes et les hypothèses sur la sélection naturelle par la peste sont présentées et les mécanismes immunitaires correspondants sont décrits lorsqu’ils sont connus. Une série d’allèles qui auraient été sélectionnés par la peste sont associés à une sensibilité accrue à d’autres maladies, mettant l’accent sur l’impact des mutations affectant les gènes liés à l’immunité. Finalement, les effets de la sélection naturelle sur le pathogène lui-même et les animaux réservoirs sont présentés