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Martin K Bakht
Martin K Bakht
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea
Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
Department of Biological Sciences, University of Windsor, Windsor, Ontario, Canada
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Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
Department of Biological Sciences, University of Windsor, Windsor, Ontario, Canada
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Iulian Derecichei
Iulian Derecichei
Department of Biological Sciences, University of Windsor, Windsor, Ontario, Canada
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Yinan Li
Yinan Li
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
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Rosa-Maria Ferraiuolo
Rosa-Maria Ferraiuolo
Department of Biological Sciences, University of Windsor, Windsor, Ontario, Canada
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Mark Dunning
Mark Dunning
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
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So Won Oh
So Won Oh
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea
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Abdulkadir Hussein
Abdulkadir Hussein
Department of Mathematics and Statistics, University of Windsor, Windsor, Ontario, Canada
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Hyewon Youn
Hyewon Youn
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea
Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, Korea
Cancer Imaging Center, Seoul National University Hospital, Seoul, Korea
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Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, Korea
Cancer Imaging Center, Seoul National University Hospital, Seoul, Korea
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Keith F Stringer
Keith F Stringer
Department of Biological Sciences, University of Windsor, Windsor, Ontario, Canada
Department of Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
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Department of Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
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Chang Wook Jeong
Chang Wook Jeong
Department of Urology, Seoul National University College of Medicine, Seoul, Korea
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Gi Jeong Cheon
Gi Jeong Cheon
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea
Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Cheol Kwak
Cheol Kwak
Department of Urology, Seoul National University College of Medicine, Seoul, Korea
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Keon Wook Kang
Keon Wook Kang
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea
Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Laboratory of Molecular Imaging and Therapy, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Alastair D Lamb
Alastair D Lamb
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
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Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
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Yuzhuo Wang
Yuzhuo Wang
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, British Columbia, Canada
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Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, British Columbia, Canada
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Xuesen Dong
Xuesen Dong
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
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Lisa A Porter
Lisa A Porter
Department of Biological Sciences, University of Windsor, Windsor, Ontario, Canada
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Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate adenocarcinoma (AdPC) cells and acts as a target for molecular imaging. However, some case reports indicate that PSMA-targeted imaging could be ineffectual for delineation of neuroendocrine (NE) prostate cancer (NEPC) lesions due to the suppression of the PSMA gene (FOLH1). These same reports suggest that targeting somatostatin receptor type 2 (SSTR2) could be an alternative diagnostic target for NEPC patients. This study evaluates the correlation between expression of FOLH1, NEPC marker genes and SSTR2. We evaluated the transcript abundance for FOLH1 and SSTR2 genes as well as NE markers across 909 tumors. A significant suppression of FOLH1 in NEPC patient samples and AdPC samples with high expression of NE marker genes was observed. We also investigated protein alterations of PSMA and SSTR2 in an NE-induced cell line derived by hormone depletion and lineage plasticity by loss of p53. PSMA is suppressed following NE induction and cellular plasticity in p53-deficient NEPC model. The PSMA-suppressed cells have more colony formation ability and resistance to enzalutamide treatment. Conversely, SSTR2 was only elevated following hormone depletion. In 18 NEPC patient-derived xenograft (PDX) models we find a significant suppression of FOLH1 and amplification of SSTR2 expression. Due to the observed FOLH1-supressed signature of NEPC, this study cautions on the reliability of using PMSA as a target for molecular imaging of NEPC. The observed elevation of SSTR2 in NEPC supports the possible ability of SSTR2-targeted imaging for follow-up imaging of low PSMA patients and monitoring for NEPC development.
Benjamin C Thomas
Benjamin C Thomas
Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
Biomarker Initiative, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
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Biomarker Initiative, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
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Jonathan D Kay
Jonathan D Kay
Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
Biomarker Initiative, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
Molecular Diagnostics and Therapeutics Group, University College London, London, UK
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Biomarker Initiative, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
Molecular Diagnostics and Therapeutics Group, University College London, London, UK
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Suraj Menon
Suraj Menon
Bioinformatics and Statistics Core Facility, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
Astra Zeneca, 2 Riverside, Granta Park, Cambridge, UK
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Astra Zeneca, 2 Riverside, Granta Park, Cambridge, UK
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Sarah L Vowler
Sarah L Vowler
Bioinformatics and Statistics Core Facility, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
Astra Zeneca, 2 Riverside, Granta Park, Cambridge, UK
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Astra Zeneca, 2 Riverside, Granta Park, Cambridge, UK
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Sarah N Dawson
Sarah N Dawson
Bioinformatics and Statistics Core Facility, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
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Laura J Bucklow
Laura J Bucklow
Biomarker Initiative, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
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Hayley J Luxton
Hayley J Luxton
Biomarker Initiative, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
Molecular Diagnostics and Therapeutics Group, University College London, London, UK
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Molecular Diagnostics and Therapeutics Group, University College London, London, UK
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Thomas Johnston
Thomas Johnston
Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
Biomarker Initiative, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
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Biomarker Initiative, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
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Charlie E Massie
Charlie E Massie
Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
Molecular and Computational Diagnostics Group, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
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Molecular and Computational Diagnostics Group, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
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Michelle Pugh
Michelle Pugh
Genomics Core Facility, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
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Anne Y Warren
Anne Y Warren
Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Peter Barker
Peter Barker
National Institute for Health Research Cambridge Biomedical Research Centre Core Biochemistry Assay Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Keith Burling
Keith Burling
National Institute for Health Research Cambridge Biomedical Research Centre Core Biochemistry Assay Laboratory, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Andy G Lynch
Andy G Lynch
Computational Biology Group, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
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Anne George
Anne George
Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
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Johanna Burge
Johanna Burge
Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
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Marie Corcoran
Marie Corcoran
Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
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Sara Stearn
Sara Stearn
Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
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Alastair D Lamb
Alastair D Lamb
Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
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Naomi L Sharma
Naomi L Sharma
Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
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Greg L Shaw
Greg L Shaw
Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
University College Hospital at Westmoreland Street, London, UK
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University College Hospital at Westmoreland Street, London, UK
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David E Neal
David E Neal
Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
Nuffield Department of Surgical Sciences, John Radcliffe Hospital, Headington, Oxford, UK
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Nuffield Department of Surgical Sciences, John Radcliffe Hospital, Headington, Oxford, UK
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Hayley C Whitaker
Hayley C Whitaker
Uro-Oncology Research Group, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
Biomarker Initiative, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
Molecular Diagnostics and Therapeutics Group, University College London, London, UK
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Biomarker Initiative, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
Molecular Diagnostics and Therapeutics Group, University College London, London, UK
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Due to increased sensitivity, the expression of circulating nucleotides is rapidly gaining popularity in cancer diagnosis. Whole blood mRNA has been used in studies on a number of cancers, most notably two separate studies that used whole blood mRNA to define non-overlapping signatures of prostate cancer that has become castration independent. Prostate cancer is known to rely on androgens for initial growth, and there is increasing evidence on the importance of the androgen axis in advanced disease. Using whole blood mRNA samples from patients with prostate cancer, we have identified the four-gene panel of FAM129A, MME, KRT7 and SOD2 in circulating mRNA that are differentially expressed in a discovery cohort of metastatic samples. Validation of these genes at the mRNA and protein level was undertaken in additional cohorts defined by risk of relapse following surgery and hormone status. All the four genes were downregulated at the mRNA level in the circulation and in primary tissue, but this was not always reflected in tissue protein expression. MME demonstrated significant differences in the hormone cohorts, whereas FAM129A is downregulated at the mRNA level but is raised at the protein level in tumours. Using published ChIP-seq data, we have demonstrated that this may be due to AR binding at the FAM129A and MME loci in multiple cell lines. These data suggest that whole blood mRNA of androgen-regulated genes has the potential to be used for diagnosis and monitoring of prostate cancer.
Charles E Massie
Charles E Massie
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
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Inmaculada Spiteri
Inmaculada Spiteri
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
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Helen Ross-Adams
Helen Ross-Adams
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
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Hayley Luxton
Hayley Luxton
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
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Jonathan Kay
Jonathan Kay
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
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Hayley C Whitaker
Hayley C Whitaker
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
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Mark J Dunning
Mark J Dunning
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
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Alastair D Lamb
Alastair D Lamb
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
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Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
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Antonio Ramos-Montoya
Antonio Ramos-Montoya
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
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Daniel S Brewer
Daniel S Brewer
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
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Colin S Cooper
Colin S Cooper
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
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Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
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Rosalind Eeles
Rosalind Eeles
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
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Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
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UK Prostate ICGC Group
UK Prostate ICGC Group
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Anne Y Warren
Anne Y Warren
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
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Simon Tavaré
Simon Tavaré
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
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David E Neal
David E Neal
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
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Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
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Andy G Lynch
Andy G Lynch
Cancer Research UK Cambridge Institute, Division of Genetics and Epidemiology, Department of Biological Sciences and School of Medicine, Royal Marsden NHS Foundation Trust, Departments of Pathology, Urology, Surgical Oncology, University of Cambridge, Cambridge, CB2 0RE, UK
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Prostate cancer is the most common cancer in men, resulting in over 10 000 deaths/year in the UK. Sequencing and copy number analysis of primary tumours has revealed heterogeneity within tumours and an absence of recurrent founder mutations, consistent with non-genetic disease initiating events. Using methylation profiling in a series of multi-focal prostate tumours, we identify promoter methylation of the transcription factor HES5 as an early event in prostate tumourigenesis. We confirm that this epigenetic alteration occurs in 86–97% of cases in two independent prostate cancer cohorts (n=49 and n=39 tumour–normal pairs). Treatment of prostate cancer cells with the demethylating agent 5-aza-2′-deoxycytidine increased HES5 expression and downregulated its transcriptional target HES6, consistent with functional silencing of the HES5 gene in prostate cancer. Finally, we identify and test a transcriptional module involving the AR, ERG, HES1 and HES6 and propose a model for the impact of HES5 silencing on tumourigenesis as a starting point for future functional studies.
