Widespread and Functional RNA Circularization in Localized Prostate Cancer

Sujun Chen¹, Vincent Huang², Xin Xu³, Julie Livingstone², Fraser Soares³, Jouhyun Jeon², Yong Zeng³, Junjie Tony Hua⁴, Jessica Petricca⁴, Haiyang Guo³, Miranda Wang³, Fouad Yousif², Yuzhe Zhang⁵, Nilgun Donmez⁶, Musaddeque Ahmed³, Stas Volik⁶, Anna Lapuk⁶, Melvin L K Chua², Lawrence E Heisler², Adrien Foucal², Natalie S Fox⁷, Michael Fraser⁸, Vinayak Bhandari⁷, Yu-Jia Shiah², Jiansheng Guan⁹, Jixi Li¹⁰, Michèle Orain¹¹, Valérie Picard¹¹, Hélène Hovington¹¹, Alain Bergeron¹¹, Louis Lacombe¹¹, Yves Fradet¹¹, Bernard Têtu¹², Stanley Liu¹³, Felix Feng¹⁴, Xue Wu¹⁵, Yang W Shao¹⁶, Malgorzata A Komor¹⁷, Cenk Sahinalp⁶, Colin Collins¹⁸, Youri Hoogstrate¹⁹, Mark de Jong²⁰, Remond J A Fijneman²¹, Teng Fei²², Guido Jenster¹⁹, Theodorus van der Kwast²³, Robert G Bristow²⁴, Paul C Boutros²⁵, Housheng Hansen He²⁶

Affiliations

¹ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
² Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
³ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
⁴ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
⁵ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; College of Life Sciences, Central China Normal University, Wuhan, Hubei, China; College of Basic Medical Sciences, Dali University, Dali, Yunnan, China.
⁶ Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
⁷ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
⁸ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
⁹ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; College of Electrical Engineering and Automation, Xiamen University of Technology, Xiamen, China.
¹⁰ State Key Laboratory of Genetic Engineering, Department of Neurology, School of Life Sciences and Huashan Hospital, Fudan University, Shanghai, China.
¹¹ Research Centre of CHU de Québec-Université Laval, Québec City, Québec, Canada.
¹² Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
¹³ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada.
¹⁴ Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA; Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
¹⁵ Translational Medicine Research Institute, Geneseeq Technology, Toronto, Ontario, Canada.
¹⁶ Translational Medicine Research Institute, Geneseeq Technology, Toronto, Ontario, Canada; School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
¹⁷ Translational Gastrointestinal Oncology, Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncoproteomics Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
¹⁸ Vancouver Prostate Centre, Vancouver, British Columbia, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁹ Department of Urology, Erasmus Medical Centre, Rotterdam, the Netherlands.
²⁰ GenomeScan, Leiden, the Netherlands.
²¹ Translational Gastrointestinal Oncology, Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
²² College of Life and Health Sciences, Northeastern University, Shenyang, China.
²³ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada.
²⁴ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; Division of Cancer Sciences, University of Manchester, Manchester, UK; The Christie NHS Foundation Trust, Manchester, UK; Manchester Cancer Research Centre, Manchester, UK.
²⁵ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, Los Angeles, CA, USA; Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: pboutros@mednet.ucla.edu.
²⁶ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. Electronic address: Hansenhe@uhnresearch.ca.

PMID: 30735634
DOI: 10.1016/j.cell.2019.01.025

Free article

Widespread and Functional RNA Circularization in Localized Prostate Cancer

Sujun Chen et al. Cell. 2019.

Free article

. 2019 Feb 7;176(4):831-843.e22.

doi: 10.1016/j.cell.2019.01.025.

Authors

Affiliations

¹ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
² Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
³ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
⁴ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
⁵ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; College of Life Sciences, Central China Normal University, Wuhan, Hubei, China; College of Basic Medical Sciences, Dali University, Dali, Yunnan, China.
⁶ Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
⁷ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
⁸ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
⁹ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; College of Electrical Engineering and Automation, Xiamen University of Technology, Xiamen, China.
¹⁰ State Key Laboratory of Genetic Engineering, Department of Neurology, School of Life Sciences and Huashan Hospital, Fudan University, Shanghai, China.
¹¹ Research Centre of CHU de Québec-Université Laval, Québec City, Québec, Canada.
¹² Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
¹³ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada.
¹⁴ Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA; Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
¹⁵ Translational Medicine Research Institute, Geneseeq Technology, Toronto, Ontario, Canada.
¹⁶ Translational Medicine Research Institute, Geneseeq Technology, Toronto, Ontario, Canada; School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
¹⁷ Translational Gastrointestinal Oncology, Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncoproteomics Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
¹⁸ Vancouver Prostate Centre, Vancouver, British Columbia, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁹ Department of Urology, Erasmus Medical Centre, Rotterdam, the Netherlands.
²⁰ GenomeScan, Leiden, the Netherlands.
²¹ Translational Gastrointestinal Oncology, Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
²² College of Life and Health Sciences, Northeastern University, Shenyang, China.
²³ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada.
²⁴ Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada; Division of Cancer Sciences, University of Manchester, Manchester, UK; The Christie NHS Foundation Trust, Manchester, UK; Manchester Cancer Research Centre, Manchester, UK.
²⁵ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, Los Angeles, CA, USA; Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: pboutros@mednet.ucla.edu.
²⁶ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. Electronic address: Hansenhe@uhnresearch.ca.

PMID: 30735634
DOI: 10.1016/j.cell.2019.01.025

Abstract

The cancer transcriptome is remarkably complex, including low-abundance transcripts, many not polyadenylated. To fully characterize the transcriptome of localized prostate cancer, we performed ultra-deep total RNA-seq on 144 tumors with rich clinical annotation. This revealed a linear transcriptomic subtype associated with the aggressive intraductal carcinoma sub-histology and a fusion profile that differentiates localized from metastatic disease. Analysis of back-splicing events showed widespread RNA circularization, with the average tumor expressing 7,232 circular RNAs (circRNAs). The degree of circRNA production was correlated to disease progression in multiple patient cohorts. Loss-of-function screening identified 11.3% of highly abundant circRNAs as essential for cell proliferation; for ∼90% of these, their parental linear transcripts were not essential. Individual circRNAs can have distinct functions, with circCSNK1G3 promoting cell growth by interacting with miR-181. These data advocate for adoption of ultra-deep RNA-seq without poly-A selection to interrogate both linear and circular transcriptomes.

Keywords: RNA-seq; biomarker; circular RNA; non-coding RNA; prostate cancer; transcriptome.

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Coming full circle in cancer.
Burgess DJ. Burgess DJ. Nat Rev Genet. 2019 Apr;20(4):191. doi: 10.1038/s41576-019-0104-8. Nat Rev Genet. 2019. PMID: 30804444 No abstract available.
Implications of the circular RNAs in localized prostate cancer.
Nigam S, Manzar N, Ateeq B. Nigam S, et al. Ann Transl Med. 2019 Sep;7(Suppl 6):S195. doi: 10.21037/atm.2019.07.23. Ann Transl Med. 2019. PMID: 31656774 Free PMC article. No abstract available.

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Widespread and Functional RNA Circularization in Localized Prostate Cancer

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Widespread and Functional RNA Circularization in Localized Prostate Cancer

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