RT Journal
A1 Smid, Marcel
A1 Wilting, Saskia M.
A1 Uhr, Katharina
A1 Rodríguez-González, F. Germán
A1 de Weerd, Vanja
A1 Prager-Van der Smissen, Wendy J.C.
A1 van der Vlugt-Daane, Michelle
A1 van Galen, Anne
A1 Nik-Zainal, Serena
A1 Butler, Adam
A1 Martin, Sancha
A1 Davies, Helen R.
A1 Staaf, Johan
A1 van de Vijver, Marc J.
A1 Richardson, Andrea L.
A1 MacGrogan, Gaëten
A1 Salgado, Roberto
A1 van den Eynden, Gert G.G.M.
A1 Purdie, Colin A.
A1 Thompson, Alastair M.
A1 Caldas, Carlos
A1 Span, Paul N.
A1 Sweep, Fred C.G.J.
A1 Simpson, Peter T.
A1 Lakhani, Sunil R.
A1 Van Laere, Steven
A1 Desmedt, Christine
A1 Paradiso, Angelo
A1 Eyfjord, Jorunn
A1 Broeks, Annegien
A1 Vincent-Salomon, Anne
A1 Futreal, Andrew P.
A1 Knappskog, Stian
A1 King, Tari
A1 Viari, Alain
A1 Børresen-Dale, Anne-Lise
A1 Stunnenberg, Hendrik G.
A1 Stratton, Mike
A1 Foekens, John A.
A1 Sieuwerts, Anieta M.
A1 Martens, John W.M.
T1 The circular RNome of primary breast cancer
JF Genome Research 
JO Genome Research 
YR 2019 
FD March 01 
VO 29 
IS 3 
SP 356 
OP 366 
DO 10.1101/gr.238121.118 
UL http://genome.cshlp.org/content/29/3/356.abstract 
AB 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.