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Clin Cancer Res. 2017 Nov 15;23(22):7072-7083. doi: 10.1158/1078-0432.CCR-17-0413. Epub 2017 Sep 12.

TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup.

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Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York.
Department of Clinical Sciences, Oncology and Pathology, Lund University and Skåne University Hospital, Lund, Sweden.
GenomeDx Biosciences, Vancouver, British Columbia, Canada.
Department of Urology, Mayo Clinic, Rochester, Minnesota.
Department of Urology, Northwestern University, Illinois.
Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, Minnesota.
Department of Radiation Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
Texas Urology Specialists, Dallas, Texas.
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
Department of Radiation Oncology, University of California at San Francisco, San Francisco, California.
Department of Radiation Oncology, Michigan Center for Translational Pathology, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York.
Department of Oncologic Pathology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Massachusetts.


Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer-associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient's progression to metastatic disease.Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts (n = 1,900), two metastatic castration-resistant prostate cancer datasets (n = 293), and one prospective cohort (n = 1,385) to assess the impact of TOP2A and EZH2 expression on prostate cancer cellular program and patient outcomes. We also performed IHC staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients (n = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer-derived murine cell lines.Results: We demonstrate by genome-wide analysis of independent primary and metastatic prostate cancer datasets that concurrent TOP2A and EZH2 mRNA and protein upregulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy.Conclusions: Overall, our data support further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neoadjuvant targeted therapy approaches. Clin Cancer Res; 23(22); 7072-83. ©2017 AACR.

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