RT Journal
A1 Smid, Marcel
A1 Wilting, Saskia
A1 Uhr, Katharina
A1 Rodriguez-Gonzalez, Germán
A1 de Weerd, Vanja
A1 Prager-Van der Smissen, Wendy
A1 van der Vlugt -Daane, Michelle
A1 van Galen, Anne
A1 Nik-Zainal, Serena
A1 Butler, Adam
A1 Martin, Sancha
A1 Davies, Helen
A1 Staaf, Johan
A1 van de Vijver, Marc
A1 Richardson, Andrea
A1 MacGrogan, Gaeten
A1 Salgado, Roberto
A1 van den Eynden, Gert
A1 Purdie, Colin
A1 Thompson, Alastair
A1 Caldas, Carlos
A1 Span, Paul
A1 Sweep, Fred
A1 Simpson, Peter
A1 Lakhani, Sunil
A1 van Laere, Steven
A1 Desmedt, Christine
A1 Paradiso, Angelo
A1 Eyfjord, Jorunn
A1 Broeks, Annegien
A1 Vincent-Solomon, Anne
A1 Futreal, Andrew
A1 Knappskog, Stian
A1 King, Tara
A1 Viari, Alain
A1 Børresen-Dale, Anne-Lise
A1 Stunnenberg, Hendrik
A1 Stratton, Mike
A1 Foekens, John
A1 Sieuwerts, Anieta
A1 Martens, John
T1 The circular RNome of primary breast cancer
JF Genome Research 
JO Genome Research 
YR 2019 
FD January 28 
DO 10.1101/gr.238121.118 
SP gr.238121.118 
UL http://genome.cshlp.org/content/early/2019/01/28/gr.238121.118.abstract 
AB Circular RNAs (circRNAs) are a class of RNA 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 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.