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Genome Res. 2019 Mar;29(3):356-366. doi: 10.1101/gr.238121.118. Epub 2019 Jan 28.

The circular RNome of primary breast cancer.

Author information

1
Erasmus MC Cancer Institute and Cancer Genomics Netherlands, University Medical Center Rotterdam, Department of Medical Oncology, 3015GD Rotterdam, the Netherlands.
2
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom.
3
East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 9NB, United Kingdom.
4
Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, SE-223 81 Lund, Sweden.
5
Department of Pathology, Academic Medical Center, 1105AZ Amsterdam, the Netherlands.
6
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
7
Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
8
Département de Biopathologie, Institut Bergonié, CS 61283 33076 Bordeaux, France.
9
Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, B-1000 Brussels, Belgium.
10
Department of Pathology/TCRU GZA, 2610 Antwerp, Belgium.
11
Molecular Immunology Unit, Jules Bordet Institute, B-1000 Brussels, Belgium.
12
Department of Pathology, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom.
13
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom.
14
Department of Radiation Oncology, and Department of Laboratory Medicine, Radboud University Medical Center, 6525GA Nijmegen, the Netherlands.
15
Department of Laboratory Medicine, Radboud University Medical Center, 6525GA Nijmegen, the Netherlands.
16
Centre for Clinical Research, Faculty of Medicine, The University of Queensland, 4029 Brisbane, Australia.
17
Pathology Queensland, The Royal Brisbane and Women's Hospital, 4029 Brisbane, Australia.
18
Center for Oncological Research, University of Antwerp, 2610 Antwerp, Belgium.
19
Istituto Tumori G Paolo II, IRCCS, 70124 Bari, Italy.
20
Cancer Research Laboratory, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
21
The Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands.
22
Institut Curie, Department of Pathology and INSERM U934, 75248 Paris Cedex 05, France.
23
Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77230, USA.
24
Department of Clinical Science, University of Bergen, 5020 Bergen, Norway.
25
Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway.
26
Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
27
Synergie Lyon Cancer, Centre Léon Bérard, Lyon Cedex 08, France.
28
Equipe Erable, INRIA Grenoble-Rhône-Alpes, 38330 Montbonnot-Saint Martin, France.
29
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radiumhospital, 0310 Oslo, Norway.
30
K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, 0310 Oslo, Norway.
31
Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525GA Nijmegen, the Netherlands.

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.

PMID:
30692147
PMCID:
PMC6396421
[Available on 2019-09-01]
DOI:
10.1101/gr.238121.118

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