The circular RNome of primary breast cancer
Open accessAbstract
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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Cancer cells have probably exploited mechanisms of RNA Pol II speed regulation given the variety of circular and read-through RNAs whose expression is affected during cancer progression.
“Cancer cells have probably exploited such mechanisms given the variety of circular and read‐through RNAs whose expression is affected during cancer progression (Grosso et al, 2015; Smid et al, 2019).”
From RNA polymerase II speed: a key player in controlling and adapting transcriptome composition (2021) · cites this paper as Smid et al, 2019
The Abstract (page unavailable) reports diverse circular RNAs in breast cancer, with expression profiles associated with tumor subgroups and clinical features. It does not establish that cancer cells exploit RNA Pol II speed regulation or report changes in read-through RNA expression during cancer progression; its progression finding concerns survival after therapy. (LLM, conf=0.85)
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Cites
STAR: ultrafast universal RNA-seq aligner
Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013) · Bioinformatics · doi:10.1093/bioinformatics/bts635 · Cited by 51,709 · see citing works
Analyzing real-time PCR data by the comparative CT method
Schmittgen, T. D., & Livak, K. J. (2008) · Nature Protocols · doi:10.1038/nprot.2008.73 · Cited by 26,190 · see citing works
Signatures of mutational processes in human cancer
Initiative, A. P. C. G., Alexandrov, L. B., ICGC Breast Cancer Consortium, ICGC MMML-Seq Consortium, PedBrain, I., Nik-Zainal, S., Wedge, D. C., Aparicio, S. A. J. R., Behjati, S., Biankin, A. V., et al. (2013) · Nature · doi:10.1038/nature12477 · Cited by 9,660 · see citing works
Self-citationCircular RNAs are a large class of animal RNAs with regulatory potency
Memczak, S., Jens, M., Elefsinioti, A., Torti, F., Krueger, J., Rybak, A., Maier, L., Mackowiak, S. D., Gregersen, L. H., Munschauer, M., et al. (2013) · Nature · doi:10.1038/nature11928 · Cited by 7,990 · see citing works
Natural RNA circles function as efficient microRNA sponges
Hansen, T. B., Jensen, T. I., Clausen, B. H., Bramsen, J. B., Finsen, B., Damgaard, C. K., & Kjems, J. (2013) · Nature · doi:10.1038/nature11993 · Cited by 7,985 · see citing works
A scaling normalization method for differential expression analysis of RNA-seq data
Robinson, M. D., & Oshlack, A. (2010) · Genome Biology · doi:10.1186/gb-2010-11-3-r25 · Cited by 7,876 · see citing works
Estimating the Number of Clusters in a Data Set Via the Gap Statistic
Tibshirani, R., Walther, G., & Hastie, T. (2001) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/1467-9868.00293 · Cited by 6,205 · see citing works
Circular RNAs are abundant, conserved, and associated with ALU repeats
Jeck, W. R., Sorrentino, J. A., Wang, K., Slevin, M. K., Burd, C. E., Liu, J., Marzluff, W. F., & Sharpless, N. E. (2013) · RNA · doi:10.1261/rna.035667.112 · Cited by 4,388 · see citing works
Exon-intron circular RNAs regulate transcription in the nucleus
Li, Z., Huang, C., Bao, C., Chen, L., Lin, M., Wang, X., Zhong, G., Yu, B., Hu, W., Dai, L., et al. (2015) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2959 · Cited by 2,905 · see citing works
Salzman, J., Gawad, C., Wang, P. L., Lacayo, N. J., & Brown, P. O. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030733 · Cited by 2,457 · see citing works
Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed
Rybak-Wolf, A., Stottmeister, C., Glažar, P., Jens, M., Pino, N., Giusti, S., Hanan, M., Behm, M., Bartok, O., Ashwal-Fluss, R., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.03.027 · Cited by 2,423 · cited 4× · see citing works
“Rybak-Wolf and colleagues reported (Rybak-Wolf et al. 2015) 4522 circRNAs in the mammalian brain that were evolutionarily conserved be-”
InfluentialMassive genomic rearrangement acquired in a single catastrophic event during cancer development
Stephens, P. J., Greenman, C. D., Fu, B., Yang, F., Bignell, G. R., Mudie, L. J., Pleasance, E. D., Lau, K. W., Beare, D., Stebbings, L. A., et al. (2011) · Cell · doi:10.1016/j.cell.2010.11.055 · Cited by 2,414 · see citing works
Self-citationSambamba: fast processing of NGS alignment formats
Tarasov, A., Vilella, A. J., Cuppen, E. P. J. G., Nijman, I. J., & Prins, P. (2015) · Bioinformatics · doi:10.1093/bioinformatics/btv098 · Cited by 2,339 · see citing works
Landscape of somatic mutations in 560 breast cancer whole-genome sequences
Nik-Zainal, S., Davies, H., Staaf, J., Ramakrishna, M., Glodzik, D., Zou, X., Martincorena, I., Alexandrov, L. B., Martin, S., Wedge, D. C., et al. (2016) · Nature · doi:10.1038/nature17676 · Cited by 2,218 · see citing works
Self-citationCircular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis
Li, Y., Zheng, Q., Bao, C., Li, S., Guo, W., Zhao, J., Chen, D., Gu, J., He, X., & Huang, S. (2015) · Cell Research · doi:10.1038/cr.2015.82 · Cited by 2,210 · see citing works
Complementary Sequence-Mediated Exon Circularization
Zhang, X.-O., Wang, H.-B., Zhang, Y., Lu, X., Chen, L.-L., & Yang, L. (2014) · Cell · doi:10.1016/j.cell.2014.09.001 · Cited by 1,999 · cited 3× · see citing works
“Confirming previously reported re-sults (Jeck et al. 2013; Zhang et al. 2014; Ivanov et al. 2015), Figure 2C shows that introns next to circRNA regions are significantly larger than introns not adjacent to circRNAs: on average 2.33 and 2.27 times larger, respectively, for introns upstream of and…”
InfluentialCell-Type Specific Features of Circular RNA Expression
Salzman, J., Chen, R. E., Olsen, M. N., Wang, P. L., & Brown, P. O. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003777 · Cited by 1,955 · see citing works
Mutational Processes Molding the Genomes of 21 Breast Cancers
Nik-Zainal, S., Alexandrov, L. B., Wedge, D. C., Van Loo, P., Greenman, C. D., Raine, K., Jones, D., Hinton, J., Marshall, J., Stebbings, L. A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.04.024 · Cited by 1,909 · see citing works
Self-citationExpanded identification and characterization of mammalian circular RNAs
Guo, J. U., Agarwal, V., Guo, H., & Bartel, D. P. (2014) · Genome biology · doi:10.1186/s13059-014-0409-z · Cited by 1,578 · see citing works
Circular RNAs in cancer: opportunities and challenges in the field
Kristensen, L. S., Hansen, T. B., Venø, M. T., & Kjems, J. (2017) · Oncogene · doi:10.1038/onc.2017.361 · Cited by 1,328 · see citing works
Analysis of Intron Sequences Reveals Hallmarks of Circular RNA Biogenesis in Animals
Ivanov, A., Memczak, S., Wyler, E., Torti, F., Porath, H. T., Orejuela, M. R., Piechotta, M., Levanon, E. Y., Landthaler, M., Dieterich, C., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.12.019 · Cited by 1,092 · see citing works
The Evolutionary Landscape of Alternative Splicing in Vertebrate Species
Barbosa-Morais, N. L., Irimia, M., Pan, Q., Xiong, H. Y., Gueroussov, S., Lee, L. J., Slobodeniuc, V., Kutter, C., Watt, S., Çolak, R., et al. (2012) · Science · doi:10.1126/science.1230612 · Cited by 1,063 · see citing works
Electron microscopic evidence for the circular form of RNA in the cytoplasm of eukaryotic cells
HSU, M.-T., & COCA-PRADOS, M. (1979) · Nature · doi:10.1038/280339a0 · Cited by 1,021 · see citing works
Evolutionary Dynamics of Gene and Isoform Regulation in Mammalian Tissues
Merkin, J., Russell, C., Chen, P., & Burge, C. B. (2012) · Science · doi:10.1126/science.1228186 · Cited by 972 · see citing works
Subtypes of Breast Cancer Show Preferential Site of Relapse
Smid, M., Wang, Y., Zhang, Y., Sieuwerts, A. M., Yu, J. X., Klijn, J. G. M., Foekens, J. A., & Martens, J. W. M. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5644 · Cited by 817 · see citing works
Self-citationDetecting circular RNAs: bioinformatic and experimental challenges
Szabo, L. A., & Salzman, J. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.114 · Cited by 684 · see citing works
Efficient backsplicing produces translatable circular mRNAs
Wang, Y., & Wang, Z. (2014) · RNA · doi:10.1261/rna.048272.114 · Cited by 665 · see citing works
The Landscape of MicroRNA, Piwi-Interacting RNA, and Circular RNA in Human Saliva
Bahn, J. H., Zhang, Q., Li, F., Chan, T.-M., Lin, X., Kim, Y. D., Wong, D. T., & Xiao, X. G. (2014) · Clinical Chemistry · doi:10.1373/clinchem.2014.230433 · Cited by 658 · see citing works
Pruitt, K. D., Harrow, J., Harte, R., Wallin, C., Diekhans, M., Maglott, D. R., Searle, S. M. J., Farrell, C. M., Loveland, J. E., Ruef, B. J., et al. (2009) · Genome Research · doi:10.1101/gr.080531.108 · Cited by 558 · see citing works
Relation of a hypoxia metagene derived from head and neck cancer to prognosis of multiple cancers
Winter, S. C., Buffa, F. M., Silva, P., Miller, C., Valentine, H. R., Turley, H., Shah, K. A., Cox, G. J., Corbridge, R. J., Homer, J. J., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-3322 · Cited by 410 · see citing works
Foekens, J. A., Sieuwerts, A. M., Smid, M., Look, M. P., de Weerd, V., Boersma, A. W. M., Klijn, J. G. M., Wiemer, E. A. C., & Martens, J. W. M. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0803304105 · Cited by 370 · see citing works
Self-citationLiang, H., Zhang, X.-Z., Liu, B., Jia, G., & Li, W. (2017) · PubMed Central · Cited by 329 · see citing works
The pro-metastasis effect of circANKS1B in breast cancer
Zeng, K., He, B., Yang, B. B., Xu, T., Chen, X., Xu, M., Liu, X., Sun, H., Pan, Y., & Wang, S. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0914-x · Cited by 319 · see citing works
CoMEt: a statistical approach to identify combinations of mutually exclusive alterations in cancer
Leiserson, M. D. M., Wu, H.-T., Vandin, F., & Raphael, B. J. (2015) · Genome biology · doi:10.1186/s13059-015-0700-7 · Cited by 202 · see citing works
A stromal gene signature associated with inflammatory breast cancer
Boersma, B. J., Reimers, M., Yi, M., Ludwig, J. A., Luke, B. T., Stephens, R. M., Yfantis, H. G., Lee, D. H., Weinstein, J. N., & Ambs, S. (2007) · International Journal of Cancer · doi:10.1002/ijc.23237 · Cited by 174 · see citing works
Circular RNAs and their associations with breast cancer subtypes
Nair, A., Niu, N., Tang, X., Thompson, K. J., Wang, L., Kocher, J., Subramanian, S., & Kalari, K. R. (2016) · Oncotarget · doi:10.18632/oncotarget.13134 · Cited by 161 · see citing works
Chromothripsis and Human Disease: Piecing Together the Shattering Process
Maher, C. A., & Wilson, R. K. (2012) · Cell · doi:10.1016/j.cell.2012.01.006 · Cited by 159 · see citing works
Wang, H., Xiao, Y., Wu, L., & Ma, D. (2018) · International Journal of Oncology · doi:10.3892/ijo.2018.4265 · Cited by 150 · see citing works
Liu, Y., Lu, C., Zhou, Y., Zhang, Z., & Li, S. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.05.166 · Cited by 121 · see citing works
MicroRNA-7: a promising new target in cancer therapy
Zhao, J., Tao, Y., Zhou, Y., Qin, N., Chen, C., Tian, D., & Xu, L. (2015) · Cancer Cell International · doi:10.1186/s12935-015-0259-0 · Cited by 118 · see citing works
Smid, M., Rodríguez-González, F. G., Sieuwerts, A. M., Salgado, R., der Smissen, W. J. C. P., van der Vlugt‐Daane, M., van Galen, A., Nik‐Zainal, S., Staaf, J., Brinkman, A. B., et al. (2016) · Nature Communications · doi:10.1038/ncomms12910 · Cited by 104 · see citing works
Self-citationSieuwerts, A. M., Gelder, M. E. M., Timmermans, M. A. M., Trapman-Jansen, A., Garcia, R. R., Arnold, M., Goedheer, A. J. W., Portengen, H., Klijn, J. G. M., & Foekens, J. A. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-0560 · Cited by 85 · see citing works
Self-citationGenomic profiling of CHEK2*1100delC-mutated breast carcinomas
Massink, M. P. G., Kooi, I. E., Martens, J. W. M., Waisfisz, Q., & Meijers-Heijboer, H. E. J. (2015) · BMC Cancer · doi:10.1186/s12885-015-1880-y · Cited by 59 · see citing works
Self-citationLuminal breast cancer-specific circular RNAs uncovered by a novel tool for data analysis
Tarrero, L. C., Ferrero, G., Miano, V., Intinis, C. D., Ricci, L., Arigoni, M., Riccardo, F., Annaratone, L., Castellano, I., Calogero, R., et al. (2018) · Oncotarget · doi:10.18632/oncotarget.24522 · Cited by 34 · see citing works
Sieuwerts, A. M., Lyng, M., Gelder, M. E. M., et al. (2014) · Molecular Oncology · doi:10.1016/j.molonc.2014.07.003 · Cited by 19 · see citing works
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Kristensen, L. S., Andersen, M. S., Stagsted, L. V. W., Ebbesen, K. K., Hansen, T. B., & Kjems, J. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0158-7 · Cited by 4,823 · see citing works
Exosomes: key players in cancer and potential therapeutic strategy
Dai, J., Su, Y., Zhong, S., Cong, L., Liu, B., Yang, J., Tao, Y., He, Z., Chen, C., & Jiang, Y. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00261-0 · Cited by 1,186 · see citing works
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“Cancer cells have probably exploited such mechanisms given the variety of circular and read-through RNAs whose expression is affected during cancer progression (Grosso et al , 2015; Smid et al , 2019).”
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- Authors
- Smid, M., Wilting, S. M., Uhr, K., Rodríguez-González, F. G., de Weerd, V., Prager-Van der Smissen, W. J. C., van der Vlugt-Daane, M., van Galen, A., Nik-Zainal, S., Butler, A., Martin, S., Davies, H. R., Staaf, J., van de Vijver, M. J., Richardson, A. L., MacGrogan, G., Salgado, R., van den Eynden, G. G. G. M., Purdie, C. A., Thompson, A. M., Caldas, C., Span, P. N., Sweep, F. C. G. J., Simpson, P. T., Lakhani, S. R., Van Laere, S., Desmedt, C., Paradiso, A., Eyfjord, J., Broeks, A., Vincent-Salomon, A., Futreal, A. P., Knappskog, S., King, T., Viari, A., Børresen-Dale, A.-L., Stunnenberg, H. G., Stratton, M., Foekens, J. A., Sieuwerts, A. M., & Martens, J. W. M.
- Affiliations
- Erasmus MC (NL)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Wellcome Sanger Institute (GB)
- Lund University (SE)
- Brigham and Women's Hospital (US)
- Institut Bergonié (FR)
- Université Libre de Bruxelles (BE)
- Ninewells Hospital (GB)
- University of Cambridge (GB)
- Radboud University Medical Center (NL)
- The University of Queensland (AU)
- Istituto Tumori Bari (IT)
- University of Iceland (IS)
- The Netherlands Cancer Institute (NL)
- The University of Texas MD Anderson Cancer Center (US)
- Haukeland University Hospital (NO)
- Memorial Sloan Kettering Cancer Center (US)
- Institut national de recherche en sciences et technologies du numérique (FR)
- Radboud University Nijmegen (NL)
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2019-01-28
- Volume
- 29
- Issue
- 3
- Pages
- 356-366
- ISSN
- 1088-9051 (ISSN-L)
- 1549-5469
- PMC
- PMC6396421
- OpenAlex
- W6963131477
- Cited by
- 105
- References
- 45
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 6 · 2023: 17 · 2022: 22 · 2021: 19 · 2020: 19 · 2019: 9
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- HAL (submittedVersion, other-oa)
- Lirias (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- NORA - Norwegian Open Research Archives (submittedVersion, cc-by-nc)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
- Discovery Research Portal (University of Dundee) (submittedVersion, other-oa)
- Lund University Publications (Lund University) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Opin vísindi (Opin vísindi) (submittedVersion, cc-by-nc)
- Radboud Repository (Radboud University) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by-nc)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Apollo
- Funders
- ICGC Breast Cancer Working group by the Breast Cancer Somatic Genetics Study
- European Community's Seventh Framework Programme (FP7/2010-2014, 242006)
- Wellcome Trust (077012/Z/05/Z)
- BASIS
- ERC (ERC-2012-AdG-322737, ERC-2017-PoC-767854)
- Daniel den Hoed Foundation
- Wellcome Beit Fellow
- Wellcome Trust Intermediate Fellowship (WT100183MA)
- Dana-Farber/Harvard Cancer Center SPORE in Breast Cancer (NIH/NCI 5 P50 CA168504-02)
- Cancer Genomics Netherlands
- Netherlands Organization of Scientific research (EU-FP7-DDR)
- Breast Cancer Research Foundation
- The Icelandic Centre for Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Circular RNAs in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- circular RNA, primary breast cancer, circRNA identification, circRNA expression profiling, breast cancer subtypes, cell proliferation, siRNA knockdown, cell viability, aromatase inhibitor therapy, progression-free survival, cell-free RNA, plasma biomarkers, advanced breast cancer
- MeSH terms
- RNA, Circular, Breast Neoplasms, Carrier Proteins, Female, Humans, Lymphatic Metastasis, Repressor Proteins, RNA, Biomarkers, Tumor, CREB-Binding Protein, Transcriptome, MCF-7 Cells
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