Year: 2019
Type: preprint
Study design: Observational Study
Abstract: Circular RNAs (circRNAs) are a class of RNAs that is under increasing scrutiny, although their functional roles are debated. We analyzed RNA-seq data of 348 primary breast cancers and developed a method to identify circRNAs that does not rely on unmapped reads or known splice junctions. We identified 95,843 circRNAs, of which 20,441 were found recurrently. Of the circRNAs that match exon boundaries of the same gene, 668 showed a poor or even negative (R < 0.2) correlation with the expression level of the linear gene. In silico analysis showed only a minority (8.5%) of circRNAs could be explained by known splicing events. Both these observations suggest that specific regulatory processes for circRNAs exist. We confirmed the presence of circRNAs of CNOT2, CREBBP, and RERE in an independent pool of primary breast cancers. We identified circRNA profiles associated with subgroups of breast cancers and with biological and clinical features, such as amount of tumor lymphocytic infiltrate and proliferation index. siRNA-mediated knockdown of circCNOT2 was shown to significantly reduce viability of the breast cancer cell lines MCF-7 and BT-474, further underlining the biological relevance of circRNAs. Furthermore, we found that circular, and not linear, CNOT2 levels are predictive for progression-free survival time to aromatase inhibitor (AI) therapy in advanced breast cancer patients, and found that circCNOT2 is detectable in cell-free RNA from plasma. We showed that circRNAs are abundantly present, show characteristics of being specifically regulated, are associated with clinical and biological properties, and thus are relevant in breast cancer.
Source: Genome Research
Authors: Marcel Smid, Saskia M. Wilting, Katharina Uhr, F. Germán Rodríguez-González, Vanja de Weerd, Wendy J.C. Prager-Van der Smissen, Michelle van der Vlugt-Daane, Anne van Galen, Serena Nik-Zainal, Adam Butler, Sancha Martin, Helen R. Davies, Johan Staaf, Marc J. van de Vijver, Andrea L. Richardson, Gaëten MacGrogan, Roberto Salgado, Gert G.G.M. van den Eynden, Colin A. Purdie, Alastair M. Thompson, Carlos Caldas, Paul N. Span, Fred C.G.J. Sweep, Peter T. Simpson, Sunil R. Lakhani, Steven Van Laere, Christine Desmedt, Angelo Paradiso, Jorunn Eyfjord, Annegien Broeks, Anne Vincent-Salomon, Andrew P. Futreal, Stian Knappskog, Tari King, Alain Viari, Anne-Lise Børresen-Dale, Hendrik G. Stunnenberg, Mike Stratton, John A. Foekens, Anieta M. Sieuwerts, John W.M. Martens
Institutions: Erasmus MC, Erasmus MC Cancer Institute, Cambridge University Hospitals NHS Foundation Trust, Wellcome Sanger Institute, Lund University, Amsterdam UMC Location University of Amsterdam, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Institut Bergonié, Université Libre de Bruxelles, Institut Jules Bordet, GZA Ziekenhuizen Campus Sint-Augustinus, Ninewells Hospital, University of Cambridge, Cancer Research UK, Radboud University Medical Center, The University of Queensland, Royal Brisbane and Women's Hospital, University of Antwerp, Istituto Tumori Bari, University of Iceland, The Netherlands Cancer Institute, Inserm, Institut Curie, The University of Texas MD Anderson Cancer Center, Haukeland University Hospital, University of Bergen, Memorial Sloan Kettering Cancer Center, Institut national de recherche en sciences et technologies du numérique, Centre Inria de l'Université Grenoble Alpes, Centre Léon Bérard, Oslo University Hospital, University of Oslo, Radboud University Nijmegen, Radboud Institute for Molecular Life Sciences
Language: English
Topic: Circular RNAs in diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Funders: Breast Cancer Research Foundation, Dana-Farber/Harvard Cancer Center, Wellcome Trust, European Bioinformatics Institute, Cancer Research UK, National Institute for Health and Care Research, European Commission, Icelandic Centre for Research, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Rannís, Benelux Association for Stable Isotope Scientists, National Institutes of Health, National Cancer Institute, H2020 European Research Council, FP7 Ideas: European Research Council
Awards: G2132831713, NIHR Senior Investigator Award, NIHR Senior Investigator Award, G3640800619, Cancer Responsiveness Monitoring based on Resistance mutations in CTCs, Identification and functional validation of drugable targets/pathways for triple negative breast cancer, Breast Cancer Somatic Genetics Study, G6238179109, G7212898136, G7388744371, G8072394548, G813134719, G8209230444, G8749953402, Triple negative breast cancer control through synergistic inhibition of EGFR and CDK9 signaling, Cancer Center Support Grant, Dana Farber/Harvard Cancer Center Specialized Program of Research Excellence in Breast Cancer
OpenAlex ID: W6963131477