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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 356-366 |
| Number of pages | 11 |
| Journal | Genome Research |
| Volume | 29 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2019 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
The circular RNome of primary breast cancer. / Smid, Marcel; Wilting, Saskia M.; Uhr, Katharina; Rodríguez-González, F. Germán; De Weerd, Vanja; Prager-Van Der Smissen, Wendy J.C.; Van Der Vlugt-Daane, Michelle; Van Galen, Anne; Nik-Zainal, Serena; Butler, Adam; Martin, Sancha; Davies, Helen R.; Staaf, Johan; Van De Vijver, Marc J.; Richardson, Andrea; MacGrogan, Gaëten; Salgado, Roberto; Van Den Eynden, Gert G.G.M.; Purdie, Colin A.; Thompson, Alastair M.; Caldas, Carlos; Span, Paul N.; Sweep, Fred C.G.J.; Simpson, Peter T.; Lakhani, Sunil R.; Van Laere, Steven; Desmedt, Christine; Paradiso, Angelo; Eyfjord, Jorunn; Broeks, Annegien; Vincent-Salomon, Anne; Futreal, Andrew P.; Knappskog, Stian; King, Tari; Viari, Alain; Børresen-Dale, Anne Lise; Stunnenberg, Hendrik G.; Stratton, Mike; Foekens, John A.; Sieuwerts, Anieta M.; Martens, John W.M.
In: Genome Research, Vol. 29, No. 3, 01.03.2019, p. 356-366.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The circular RNome of primary breast cancer
AU - Smid, Marcel
AU - Wilting, Saskia M.
AU - Uhr, Katharina
AU - Rodríguez-González, F. Germán
AU - De Weerd, Vanja
AU - Prager-Van Der Smissen, Wendy J.C.
AU - Van Der Vlugt-Daane, Michelle
AU - Van Galen, Anne
AU - Nik-Zainal, Serena
AU - Butler, Adam
AU - Martin, Sancha
AU - Davies, Helen R.
AU - Staaf, Johan
AU - Van De Vijver, Marc J.
AU - Richardson, Andrea
AU - MacGrogan, Gaëten
AU - Salgado, Roberto
AU - Van Den Eynden, Gert G.G.M.
AU - Purdie, Colin A.
AU - Thompson, Alastair M.
AU - Caldas, Carlos
AU - Span, Paul N.
AU - Sweep, Fred C.G.J.
AU - Simpson, Peter T.
AU - Lakhani, Sunil R.
AU - Van Laere, Steven
AU - Desmedt, Christine
AU - Paradiso, Angelo
AU - Eyfjord, Jorunn
AU - Broeks, Annegien
AU - Vincent-Salomon, Anne
AU - Futreal, Andrew P.
AU - Knappskog, Stian
AU - King, Tari
AU - Viari, Alain
AU - Børresen-Dale, Anne Lise
AU - Stunnenberg, Hendrik G.
AU - Stratton, Mike
AU - Foekens, John A.
AU - Sieuwerts, Anieta M.
AU - Martens, John W.M.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85062091770&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062091770&partnerID=8YFLogxK
U2 - 10.1101/gr.238121.118
DO - 10.1101/gr.238121.118
M3 - Article
C2 - 30692147
AN - SCOPUS:85062091770
VL - 29
SP - 356
EP - 366
JO - Genome Research
JF - Genome Research
SN - 1088-9051
IS - 3
ER -