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Cell. 2019 Feb 7;176(4):831-843.e22. doi: 10.1016/j.cell.2019.01.025.

Widespread and Functional RNA Circularization in Localized Prostate Cancer.

Author information

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.

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

Comment in

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

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