J Cancer 2015; 6(11):1160-1171. doi:10.7150/jca.13397

Research Paper

Identification and Validation of a Five MicroRNA Signature Predictive of Prostate Cancer Recurrence and Metastasis: A Cohort Study

Robert K. Nam1✉, Yutaka Amemiya2, Tania Benatar2, Christopher J.D. Wallis1, Jessica Stojcic-Bendavid1, Stephanie Bacopulos2, Christopher Sherman3, Linda Sugar3, Magda Naeim3, Wenyi Yang2, Aiguo Zhang2, Laurence H. Klotz1, Steven A. Narod4, Arun Seth2✉

1. Division of Urology, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave., Toronto, ON, M4N3M5, Canada.
2. Department of Anatomic Pathology, Platform Biological Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave., Toronto, ON, M4N3M5, Canada.
3. Department of Laboratory Medicine and Pathobiology, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave., Toronto, ON, M4N3M5, Canada.
4. Department of Public Health Sciences, University of Toronto, 790 Bay St., Toronto, ON, M5G 1N8, Canada.

Abstract

Background: MicroRNA (miRNA) have been shown to be important in regulating gene expression in prostate cancer. We used next generation miRNA sequencing to conduct a whole miRNome analysis to identify miRNAs associated with prostate cancer metastasis.

Methods: We conducted discovery and validation analyses of miRNAs among a total of 546 men who underwent surgery for prostate cancer using the development of metastasis as an endpoint. Genome wide analysis was conducted among the discovery group (n=31) to identify new miRNAs associated with prostate cancer metastasis. Selected miRNAs were then analyzed using qPCR on prostatectomy specimens from an independent cohort (n=515) to determine whether their expression could predict the development of metastasis after surgery. To examine the biology underlying these associations, we created prostate cancer cell lines which overexpressed miR-301a for in vitro and in vivo functional assays.

Results: We identified 33 miRNAs associated with prostate cancer metastasis and selected a panel comprising miRs-301a, 652, 454, 223 and 139 which strongly predicted metastasis (AUC=95.3%, 95%C.I.:84%-99%). Among the validation cohort, the 15-year metastasis-free survival was 77.5% (95% C.I.:63.9%-86.4%) for patients with a high miRNA panel score and 98.8% (95% C.I.:94.9%-99.7%, p<0.0001 for difference) for those with a low score. After adjusting for grade, stage, and PSA, the hazard ratio for metastasis was 4.3 (95% C.I.: 1.7-11.1, p=0.002) for patients with a high miRNA panel score, compared to those with a low score. Prostate cancer cell lines overexpressing miR-301a had in significantly higher tumor growth and metastasis in a xenograft mouse model.

Conclusions: A panel of miRNAs is associated with prostate cancer metastasis. These could be used as potential new prognostic factors in the surgical management of prostate cancer.

Keywords: MicroRNA, Prostatic neoplasms, Prostatectomy, High-throughput nucleotide sequencing

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How to cite this article:
Nam RK, Amemiya Y, Benatar T, Wallis CJD, Stojcic-Bendavid J, Bacopulos S, Sherman C, Sugar L, Naeim M, Yang W, Zhang A, Klotz LH, Narod SA, Seth A. Identification and Validation of a Five MicroRNA Signature Predictive of Prostate Cancer Recurrence and Metastasis: A Cohort Study. J Cancer 2015; 6(11):1160-1171. doi:10.7150/jca.13397. Available from http://www.jcancer.org/v06p1160.htm