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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 and Butler, Adam, et al. (2019) In Genome Research 29(3). p.356-366
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... (More)

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.

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Genome Research
volume
29
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3
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11 pages
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Cold Spring Harbor Laboratory Press
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  • scopus:85062091770
ISSN
1088-9051
DOI
10.1101/gr.238121.118
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English
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4e293ab2-6cbb-44a8-ba36-2e6258491a84
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2019-05-28 10:58:57
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2019-09-18 11:59:27
@article{4e293ab2-6cbb-44a8-ba36-2e6258491a84,
  abstract     = {<p>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 &lt;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.</p>},
  author       = {Smid, Marcel and Wilting, Saskia M. and Uhr, Katharina and Rodríguez-González, F. Germán and De Weerd, Vanja and Prager-Van Der Smissen, Wendy J.C. and Van Der Vlugt-Daane, Michelle and Van Galen, Anne and Nik-Zainal, Serena and Butler, Adam and Martin, Sancha and Davies, Helen R. and Staaf, Johan and Van De Vijver, Marc J. and Richardson, Andrea L. and MacGrogan, Gaëten and Salgado, Roberto and Van Den Eynden, Gert G.G.M. and Purdie, Colin A. and Thompson, Alastair M. and Caldas, Carlos and Span, Paul N. and Sweep, Fred C.G.J. and Simpson, Peter T. and Lakhani, Sunil R. and Van Laere, Steven and Desmedt, Christine and Paradiso, Angelo and Eyfjord, Jorunn and Broeks, Annegien and Vincent-Salomon, Anne and Futreal, Andrew P. and Knappskog, Stian and King, Tari and Viari, Alain and Børresen-Dale, Anne Lise and Stunnenberg, Hendrik G. and Stratton, Mike and Foekens, John A. and Sieuwerts, Anieta M. and Martens, John W.M.},
  issn         = {1088-9051},
  language     = {eng},
  month        = {03},
  number       = {3},
  pages        = {356--366},
  publisher    = {Cold Spring Harbor Laboratory Press},
  series       = {Genome Research},
  title        = {The circular RNome of primary breast cancer},
  url          = {http://dx.doi.org/10.1101/gr.238121.118},
  volume       = {29},
  year         = {2019},
}