한빛사 논문
Jouhyun Jeon1, Ekaterina Olkhov-Mitsel2, Honglei Xie1, Cindy Q. Yao1, Fang Zhao2, Sahar Jahangiri3, Carmelle Cuizon2, Seville Scarcello3, Renu Jeyapala2, John D. Watson1, Michael Fraser1, Jessica Ray3, Kristina Commisso3, Andrew Loblaw3, Neil E. Fleshner4, Robert G. Bristow4,5,6, Michelle Downes3, Danny Vesprini3, Stanley Liu3,5,§, Bharati Bapat2,7,§, Paul C. Boutros1,5,8,9,10,11,12,13,§
1 Ontario Institute for Cancer Research, Toronto, Canada
2 Lunenfeld-Tannenbaum Research Institute, Sinai Health System, Toronto, Canada
3 Sunnybrook Research Institute and Department of Radiation Oncology, Sunnybrook-
Odette Cancer Centre, Toronto, Canada
4 Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
5 Department of Medical Biophysics, University of Toronto, Toronto, Canada
6 Manchester Cancer Research Centre, University of Manchester, Manchester, UK
7 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto,
Canada
8 Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada
9 Department of Human Genetics, University of California, Los Angeles, USA
10 Department of Urology, University of California, Los Angeles, USA
11 Broad Stem Cell Research Centre, University of California, Los Angeles, USA
12 Institute for Precision Health, University of California, Los Angeles, USA
13 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, USA
§ Corresponding authors
Paul C. Boutros, PhD. at 12-109 CHS; 10833 Le Conte Avenue; Los Angeles, CA, USA;90024
Bharati Bapat, PhD. at Lunenfeld-Tannenbaum Research Institute, 60 Murray Street, Rm
L6-304B, Toronto, ON, Canada, M5T 3L9;
Stanley Liu, PhD, MD, FRCPC at Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Rm T2-142, Toronto, ON, M4N 3M5
Abstract
Background
The development of non-invasive tests for the early detection of aggressive prostate tumours is a major unmet clinical need. miRNAs are promising non-invasive biomarkers: they play essential roles in tumourigenesis, are stable under diverse analytical conditions and can be detected in body fluids.
Methods
We measured the longitudinal stability of 673 miRNAs by collecting serial urines from 10 patients with localized prostate cancer. We then measured temporally stable miRNAs in an independent training cohort (n = 99) and created a biomarker predictive of Gleason grade using machine-learning techniques. Finally, we validated this biomarker in an independent validation cohort (n = 40).
Results
We found that each individual has a specific urine miRNA fingerprint. These fingerprints are temporally stable, and associated with specific biological functions. We identified seven miRNAs that were stable over time within individual patients, and integrated them with machine-learning techniques to create a novel biomarker for prostate cancer that overcomes inter-individual variability. Our urine biomarker robustly identified high-risk patients and achieved similar accuracy as tissue-based prognostic markers (AUC of 0.72; 95% CI = 0.69-0.76 in the training cohort, and AUC of 0.74; 95% CI = 0.55-0.92 in the validation cohort).
Conclusions
These data highlight the importance of quantifying intra- and inter-tumoural heterogeneity in biomarker development. This non-invasive biomarker may usefully supplement invasive or expensive radiologic and tissue-based assays.
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