50 results on '"Massie, Charles E."'
Search Results
2. Comprehensive characterization of cell-free tumor DNA in plasma and urine of patients with renal tumors
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Smith, Christopher G., Moser, Tina, Mouliere, Florent, Field-Rayner, Johanna, Eldridge, Matthew, Riediger, Anja L., Chandrananda, Dineika, Heider, Katrin, Wan, Jonathan C. M., Warren, Anne Y., Morris, James, Hudecova, Irena, Cooper, Wendy N., Mitchell, Thomas J., Gale, Davina, Ruiz-Valdepenas, Andrea, Klatte, Tobias, Ursprung, Stephan, Sala, Evis, Riddick, Antony C. P., Aho, Tevita F., Armitage, James N., Perakis, Samantha, Pichler, Martin, Seles, Maximilian, Wcislo, Gabriel, Welsh, Sarah J., Matakidou, Athena, Eisen, Tim, Massie, Charles E., Rosenfeld, Nitzan, Heitzer, Ellen, and Stewart, Grant D.
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- 2020
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3. Data from Measurement of Plasma Cell-Free Mitochondrial Tumor DNA Improves Detection of Glioblastoma in Patient-Derived Orthotopic Xenograft Models
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Mair, Richard, primary, Mouliere, Florent, primary, Smith, Christopher G., primary, Chandrananda, Dineika, primary, Gale, Davina, primary, Marass, Francesco, primary, Tsui, Dana W.Y., primary, Massie, Charles E., primary, Wright, Alan J., primary, Watts, Colin, primary, Rosenfeld, Nitzan, primary, and Brindle, Kevin M., primary
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- 2023
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4. Supplementary Data from Measurement of Plasma Cell-Free Mitochondrial Tumor DNA Improves Detection of Glioblastoma in Patient-Derived Orthotopic Xenograft Models
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Mair, Richard, primary, Mouliere, Florent, primary, Smith, Christopher G., primary, Chandrananda, Dineika, primary, Gale, Davina, primary, Marass, Francesco, primary, Tsui, Dana W.Y., primary, Massie, Charles E., primary, Wright, Alan J., primary, Watts, Colin, primary, Rosenfeld, Nitzan, primary, and Brindle, Kevin M., primary
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- 2023
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5. Supplementary Table 1 from Measurement of Plasma Cell-Free Mitochondrial Tumor DNA Improves Detection of Glioblastoma in Patient-Derived Orthotopic Xenograft Models
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Mair, Richard, primary, Mouliere, Florent, primary, Smith, Christopher G., primary, Chandrananda, Dineika, primary, Gale, Davina, primary, Marass, Francesco, primary, Tsui, Dana W.Y., primary, Massie, Charles E., primary, Wright, Alan J., primary, Watts, Colin, primary, Rosenfeld, Nitzan, primary, and Brindle, Kevin M., primary
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- 2023
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6. Accurate detection of benign and malignant renal tumor subtypes with MethylBoostER: An epigenetic marker-driven learning framework
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Rossi, Sabrina H, Newsham, Izzy, Pita, Sara, Brennan, Kevin, Park, Gahee, Smith, Christopher G, Lach, Radoslaw P, Mitchell, Thomas, Huang, Junfan, Babbage, Anne, Warren, Anne Y, Leppert, John T, Stewart, Grant D, Gevaert, Olivier, Massie, Charles E, Samarajiwa, Shamith A, Rossi, Sabrina H [0000-0001-7048-7158], Newsham, Izzy [0000-0003-0816-4045], Pita, Sara [0000-0002-5163-7306], Park, Gahee [0000-0002-9599-687X], Smith, Christopher G [0000-0001-7357-2737], Mitchell, Thomas [0000-0003-0761-9503], Huang, Junfan [0000-0002-3282-1722], Warren, Anne Y [0000-0002-1170-7867], Leppert, John T [0000-0001-9980-3863], Stewart, Grant D [0000-0003-3188-9140], Gevaert, Olivier [0000-0002-9965-5466], Massie, Charles E [0000-0003-2314-4843], Samarajiwa, Shamith A [0000-0003-1046-0601], and Apollo - University of Cambridge Repository
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Kidney Disease ,Multidisciplinary ,FOS: Biological sciences ,Genetics ,32 Biomedical and Clinical Sciences ,Patient Safety ,4 Detection, screening and diagnosis ,3202 Clinical Sciences ,Cancer ,4.2 Evaluation of markers and technologies - Abstract
Current gold standard diagnostic strategies are unable to accurately differentiate malignant from benign small renal masses preoperatively; consequently, 20% of patients undergo unnecessary surgery. Devising a more confident presurgical diagnosis is key to improving treatment decision-making. We therefore developed MethylBoostER, a machine learning model leveraging DNA methylation data from 1228 tissue samples, to classify pathological subtypes of renal tumors (benign oncocytoma, clear cell, papillary, and chromophobe RCC) and normal kidney. The prediction accuracy in the testing set was 0.960, with class-wise ROC AUCs >0.988 for all classes. External validation was performed on >500 samples from four independent datasets, achieving AUCs >0.89 for all classes and average accuracies of 0.824, 0.703, 0.875, and 0.894 for the four datasets. Furthermore, consistent classification of multiregion samples (N = 185) from the same patient demonstrates that methylation heterogeneity does not limit model applicability. Following further clinical studies, MethylBoostER could facilitate a more confident presurgical diagnosis to guide treatment decision-making in the future., Cancer Research UK Clinical Doctoral Fellowship. (S.H.R.) UK Medical Research Council doctoral training award. (I.N) UK Medical Research Council funding (MC UU 12022/10) (S.A.S, J.H) Isaac Newton Trust/Wellcome Trust ISSF/University of Cambridge grant (S.A.S, J.H) CRUK Fellowship award (A26718) (C.E.M.) The Mark Foundation for Cancer Research, the Cancer Research UK Cambridge Centre [C9685/A25177] and NIHR Cambridge Biomedical Research Centre (BRC- 1215-20014). (G.D.S., A.Y.W) The Human Research Tissue Bank at Addenbrooke’s Hospital is supported by the NIHR Cambridge Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
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- 2022
7. Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target
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Asim, Mohammad, Massie, Charles E., Orafidiya, Folake, Pértega-Gomes, Nelma, Warren, Anne Y., Esmaeili, Mohsen, Selth, Luke A., Zecchini, Heather I., Luko, Katarina, Qureshi, Arham, Baridi, Ajoeb, Menon, Suraj, Madhu, Basetti, Escriu, Carlos, Lyons, Scott, Vowler, Sarah L., Zecchini, Vincent R., Shaw, Greg, Hessenkemper, Wiebke, Russell, Roslin, Mohammed, Hisham, Stefanos, Niki, Lynch, Andy G., Grigorenko, Elena, D’Santos, Clive, Taylor, Chris, Lamb, Alastair, Sriranjan, Rouchelle, Yang, Jiali, Stark, Rory, Dehm, Scott M., Rennie, Paul S., Carroll, Jason S., Griffiths, John R., Tavaré, Simon, Mills, Ian G., McEwan, Iain J., Baniahmad, Aria, Tilley, Wayne D., and Neal, David E.
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- 2016
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8. Methods to Identify Chromatin-Bound Protein Complexes: From Genome-Wide to Locus-Specific Approaches
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Massie, Charles E., primary
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- 2016
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9. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer
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Asim, Mohammad, Tarish, Firas, Zecchini, Heather I., Sanjiv, Kumar, Gelali, Eleni, Massie, Charles E., Baridi, Ajoeb, Warren, Anne Y., Zhao, Wanfeng, Ogris, Christoph, McDuffus, Leigh-Anne, Mascalchi, Patrice, Shaw, Greg, Dev, Harveer, Wadhwa, Karan, Wijnhoven, Paul, Forment, Josep V., Lyons, Scott R., Lynch, Andy G., O’Neill, Cormac, Zecchini, Vincent R., Rennie, Paul S., Baniahmad, Aria, Tavaré, Simon, Mills, Ian G., Galanty, Yaron, Crosetto, Nicola, Schultz, Niklas, Neal, David, and Helleday, Thomas
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- 2017
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10. Supplement to: Effect of mutation order on myeloproliferative neoplasms.
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Ortmann, Christina A., Kent, David G., Nangalia, Jyoti, Silber, Yvonne, Wedge, David C., Grinfeld, Jacob, Baxter, Joanna E., Massie, Charles E., Papaemmanuil, Elli, Menon, Suraj, Godfrey, Anna L., Dimitropoulou, Danai, Guglielmelli, Paola, Bellosillo, Beatriz, Besses, Carles, Döhner, Konstanze, Harrison, Claire N., Vassiliou, George S., Vannucchi, Alessandro, Campbell, Peter J., and Green, Anthony R.
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- 2015
11. Effect of Mutation Order on Myeloproliferative Neoplasms
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Ortmann, Christina A., Kent, David G., Nangalia, Jyoti, Silber, Yvonne, Wedge, David C., Grinfeld, Jacob, Baxter, E. Joanna, Massie, Charles E., Papaemmanuil, Elli, Menon, Suraj, Godfrey, Anna L., Dimitropoulou, Danai, Guglielmelli, Paola, Bellosillo, Beatriz, Besses, Carles, Döhner, Konstanze, Harrison, Claire N., Vassiliou, George S., Vannucchi, Alessandro, Campbell, Peter J., and Green, Anthony R.
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- 2015
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12. Mapping Protein–DNA Interactions Using ChIP-Sequencing
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Massie, Charles E., primary and Mills, Ian G., additional
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- 2011
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13. Global Identification of Androgen Response Elements
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Massie, Charles E., primary and Mills, Ian G., additional
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- 2011
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14. Chromatin Immunoprecipitation (ChIP) Methodology and Readouts
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Massie, Charles E., primary and Mills, Ian G., additional
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- 2009
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15. Comprehensive characterisation of cell-free tumour DNA in plasma and urine of patients with renal tumours
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Smith, Christopher G, primary, Moser, Tina, additional, Burge, Johanna, additional, Eldridge, Matthew, additional, Riediger, Anja L, additional, Mouliere, Florent, additional, Chandrananda, Dineika, additional, Heider, Katrin, additional, Wan, Jonathan CM, additional, Warren, Anne Y, additional, Morris, James, additional, Hudecova, Irena, additional, Cooper, Wendy N, additional, Mitchell, Thomas J, additional, Gale, Davina, additional, Ruiz-Valdepenas, Andrea, additional, Klatte, Tobias, additional, Ursprung, Stephan, additional, Sala, Evis, additional, Riddick, Antony CP, additional, Aho, Tevita F, additional, Armitage, James N, additional, Perakis, Samantha, additional, Pichler, Martin, additional, Seles, Maximilian, additional, Wcislo, Gabriel, additional, Welsh, Sarah J, additional, Matakidou, Athena, additional, Eisen, Tim, additional, Massie, Charles E, additional, Rosenfeld, Nitzan, additional, Heitzer, Ellen, additional, and Stewart, Grant D, additional
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- 2019
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16. Measurement of Plasma Cell-Free Mitochondrial Tumor DNA Improves Detection of Glioblastoma in Patient-Derived Orthotopic Xenograft Models
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Mair, Richard, primary, Mouliere, Florent, additional, Smith, Christopher G., additional, Chandrananda, Dineika, additional, Gale, Davina, additional, Marass, Francesco, additional, Tsui, Dana W.Y., additional, Massie, Charles E., additional, Wright, Alan J., additional, Watts, Colin, additional, Rosenfeld, Nitzan, additional, and Brindle, Kevin M., additional
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- 2019
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17. Enhanced detection of circulating tumor DNA by fragment size analysis
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Mouliere, Florent, primary, Chandrananda, Dineika, additional, Piskorz, Anna M., additional, Moore, Elizabeth K., additional, Morris, James, additional, Ahlborn, Lise Barlebo, additional, Mair, Richard, additional, Goranova, Teodora, additional, Marass, Francesco, additional, Heider, Katrin, additional, Wan, Jonathan C. M., additional, Supernat, Anna, additional, Hudecova, Irena, additional, Gounaris, Ioannis, additional, Ros, Susana, additional, Jimenez-Linan, Mercedes, additional, Garcia-Corbacho, Javier, additional, Patel, Keval, additional, Østrup, Olga, additional, Murphy, Suzanne, additional, Eldridge, Matthew D., additional, Gale, Davina, additional, Stewart, Grant D., additional, Burge, Johanna, additional, Cooper, Wendy N., additional, van der Heijden, Michiel S., additional, Massie, Charles E., additional, Watts, Colin, additional, Corrie, Pippa, additional, Pacey, Simon, additional, Brindle, Kevin M., additional, Baird, Richard D., additional, Mau-Sørensen, Morten, additional, Parkinson, Christine A., additional, Smith, Christopher G., additional, Brenton, James D., additional, and Rosenfeld, Nitzan, additional
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- 2018
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18. Cholinekinase alpha as an androgen receptor chaperone and prostate cancer therapeutic target
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Asim, Mohammad, Massie, Charles E., Orafidiya, Folake, Pértega-Gomes, Nelma, Warren, Anne Y., Esmaeili, Mohsen, Selth, Luke A., Zecchini, Heather I., Luko, Katarina, Qureshi, Arham, Baridi, Ajoeb, Menon, Suraj, Madhu, Basetti, Escriu, Carlos, Lyons, Scott, Vowler, Sarah L., Zecchini, Vincent R., Shaw, Greg, Hessenkemper, Wiebke, Russell, Roslin, Mohammed, Hisham, Stefanos, Niki, Lynch, Andy G., Grigorenko, Elena, D’Santos, Clive, Taylor, Chris, Lamb, Alastair, Sriranjan, Rouchelle, Yang, Jiali, Stark, Rory, Dehm, Scott M., Rennie, Paul S., Carroll, Jason S., Griffiths, John R., Tavaré, Simon, Mills, Ian G., McEwan, Iain J., Baniahmad, Aria, Tilley, Wayne D., Neal, David E., University of St Andrews. School of Medicine, and University of St Andrews. Statistics
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RC0254 ,QH301 ,SDG 3 - Good Health and Well-being ,RC0254 Neoplasms. Tumors. Oncology (including Cancer) ,QH301 Biology ,DAS ,QH426 Genetics ,QH426 - Abstract
The RNA-seq data generated during this work has been submitted to Gene Expression Omnibus and is available for viewing at the following link http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token = ytazouoixxedjal&acc=GSE63700. Background: The androgen receptor (AR) is a major drug target in prostate cancer (PCa). We profiled the AR-regulated kinome to identify clinically relevant and druggable effectors of AR signaling. Methods: Using genome-wide approaches, we interrogated all AR regulated kinases. Among these, choline kinase alpha (CHKA) expression was evaluated in benign (n = 195), prostatic intraepithelial neoplasia (PIN) (n = 153) and prostate cancer (PCa) lesions (n = 359). We interrogated how CHKA regulates AR signaling using biochemical assays and investigated androgen regulation of CHKA expression in men with PCa, both untreated (n = 20) and treated with an androgen biosynthesis inhibitor degarelix (n = 27). We studied the effect of CHKA inhibition on the PCa transcriptome using RNA sequencing and tested the effect of CHKA inhibition on cell growth, clonogenic survival and invasion. Tumor xenografts (n = 6 per group) were generated in mice using genetically engineered prostate cancer cells with inducible CHKA knockdown. Data were analyzed with χ 2 tests, Cox regression analysis, and Kaplan-Meier methods. All statistical tests were two-sided. Results: CHKA expression was shown to be androgen regulated in cell lines, xenografts, and human tissue (log fold change from 6.75 to 6.59, P = .002) and was positively associated with tumor stage. CHKA binds directly to the ligand-binding domain (LBD) of AR, enhancing its stability. As such, CHKA is the first kinase identified as an AR chaperone. Inhibition of CHKA repressed the AR transcriptional program including pathways enriched for regulation of protein folding, decreased AR protein levels, and inhibited the growth of PCa cell lines, human PCa explants, and tumor xenografts. Conclusions:CHKA can act as an AR chaperone, providing, to our knowledge, the first evidence for kinases as molecular chaperones, making CHKA both a marker of tumor progression and a potential therapeutic target for PCa. Publisher PDF
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- 2016
19. Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target
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Asim, Mohammad, Massie, Charles E, Orafidiya, Folake, Pértega-Gomes, Nelma, Warren, Anne Y, Esmaeili, Mohsen, Selth, Luke A, Zecchini, Heather I, Luko, Katarina, Qureshi, Arham, Baridi, Ajoeb, Menon, Suraj, Madhu, Basetti, Escriu, Carlos, Lyons, Scott, Vowler, Sarah L, Zecchini, Vincent R, Shaw, Greg, Hessenkemper, Wiebke, Russell, Roslin, Mohammed, Hisham, Stefanos, Niki, Lynch, Andy G, Grigorenko, Elena, D'Santos, Clive, Taylor, Chris, Lamb, Alastair, Sriranjan, Rouchelle, Yang, Jiali, Stark, Rory, Dehm, Scott M, Rennie, Paul S, Carroll, Jason S, Griffiths, John R, Tavaré, Simon, Mills, Ian G, McEwan, Iain J, Baniahmad, Aria, Tilley, Wayne D, Neal, David E, Massie, Charles [0000-0003-2314-4843], Warren, Anne [0000-0002-1170-7867], Lynch, Andy [0000-0002-7876-7338], Stark, Rory [0000-0002-1790-5469], Carroll, Jason [0000-0003-3643-0080], Griffiths, John [0000-0001-7369-6836], and Apollo - University of Cambridge Repository
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Male ,Antineoplastic Agents ,Kaplan-Meier Estimate ,Mice, SCID ,Article ,Mice ,SDG 3 - Good Health and Well-being ,Mice, Inbred NOD ,Biomarkers, Tumor ,Animals ,Choline Kinase ,Humans ,Molecular Targeted Therapy ,Enzyme Inhibitors ,Aged ,Neoplasm Staging ,Proportional Hazards Models ,Prostatectomy ,Prostatic Neoplasms ,Sequence Analysis, DNA ,Middle Aged ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Receptors, Androgen ,Neoplasm Grading ,Molecular Chaperones ,Signal Transduction - Abstract
BACKGROUND: The androgen receptor (AR) is a major drug target in prostate cancer (PCa). We profiled the AR-regulated kinome to identify clinically relevant and druggable effectors of AR signaling.METHODS: Using genome-wide approaches, we interrogated all AR regulated kinases. Among these, choline kinase alpha (CHKA) expression was evaluated in benign (n = 195), prostatic intraepithelial neoplasia (PIN) (n = 153) and prostate cancer (PCa) lesions (n = 359). We interrogated how CHKA regulates AR signaling using biochemical assays and investigated androgen regulation of CHKA expression in men with PCa, both untreated (n = 20) and treated with an androgen biosynthesis inhibitor degarelix (n = 27). We studied the effect of CHKA inhibition on the PCa transcriptome using RNA sequencing and tested the effect of CHKA inhibition on cell growth, clonogenic survival and invasion. Tumor xenografts (n = 6 per group) were generated in mice using genetically engineered prostate cancer cells with inducible CHKA knockdown. Data were analyzed with χ(2) tests, Cox regression analysis, and Kaplan-Meier methods. All statistical tests were two-sided.RESULTS: CHKA expression was shown to be androgen regulated in cell lines, xenografts, and human tissue (log fold change from 6.75 to 6.59, P = .002) and was positively associated with tumor stage. CHKA binds directly to the ligand-binding domain (LBD) of AR, enhancing its stability. As such, CHKA is the first kinase identified as an AR chaperone. Inhibition of CHKA repressed the AR transcriptional program including pathways enriched for regulation of protein folding, decreased AR protein levels, and inhibited the growth of PCa cell lines, human PCa explants, and tumor xenografts.CONCLUSIONS: CHKA can act as an AR chaperone, providing, to our knowledge, the first evidence for kinases as molecular chaperones, making CHKA both a marker of tumor progression and a potential therapeutic target for PCa.
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- 2015
20. Selecting short DNA fragments in plasma improves detection of circulating tumour DNA
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Mouliere, Florent, primary, Piskorz, Anna M., additional, Chandrananda, Dineika, additional, Moore, Elizabeth, additional, Morris, James, additional, Smith, Christopher G., additional, Goranova, Teodora, additional, Heider, Katrin, additional, Mair, Richard, additional, Supernat, Anna, additional, Gounaris, Ioannis, additional, Ros, Susana, additional, Wan, Jonathan C. M., additional, Jimenez-Linan, Mercedes, additional, Gale, Davina, additional, Brindle, Kevin, additional, Massie, Charles E., additional, Parkinson, Christine A., additional, Brenton, James D., additional, and Rosenfeld, Nitzan, additional
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- 2017
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21. The importance of DNA methylation in prostate cancer development
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Massie, Charles E., primary, Mills, Ian G., additional, and Lynch, Andy G., additional
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- 2017
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22. Nongenetic stochastic expansion of JAK2V617F-homozygous subclones in polycythemia vera?
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Godfrey, Anna L., Nangalia, Jyoti, Baxter, E. Joanna, Massie, Charles E., Kent, David G., Papaemmanuil, Elli, Campbell, Peter J., and Green, Anthony R.
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- 2014
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23. HES5 silencing is an early and recurrent change in prostate tumourigenesis
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Massie, Charles E, Spiteri, Inmaculada, Ross-Adams, Helen, Luxton, Hayley, Kay, Jonathan, Whitaker, Hayley C, Dunning, Mark J, Lamb, Alastair D, Ramos-Montoya, Antonio, Brewer, Daniel S, Cooper, Colin S, Eeles, Rosalind, UK Prostate ICGC Group, Warren, Anne Y, Tavaré, Simon, Neal, David E, Lynch, Andy G, University of St Andrews. School of Medicine, University of St Andrews. Statistics, Massie, Charles [0000-0003-2314-4843], Dunning, Mark [0000-0002-8853-9435], Warren, Anne [0000-0002-1170-7867], Lynch, Andy [0000-0002-7876-7338], and Apollo - University of Cambridge Repository
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Male ,Cancer Research ,Carcinogenesis ,Endocrinology, Diabetes and Metabolism ,NDAS ,Methylation ,Epigenesis, Genetic ,RC0254 ,Endocrinology ,Transcriptional Regulator ERG ,SDG 3 - Good Health and Well-being ,Cell Line, Tumor ,Basic Helix-Loop-Helix Transcription Factors ,Humans ,Promoter Regions, Genetic ,Prostate cancer ,epigenetics ,RC0254 Neoplasms. Tumors. Oncology (including Cancer) ,Gene Expression Profiling ,Prostatic Neoplasms ,DNA Methylation ,prostate cancer ,Gene Expression Regulation, Neoplastic ,Repressor Proteins ,NOTCH ,Oncology ,ERG ,Trans-Activators ,Epigenetics ,methylation ,HES6 ,HES5 ,AR - Abstract
The ICGC Prostate UK Group is funded by Cancer Research UK Grant C5047/A14835, by the Dallaglio Foundation, and by The Wellcome Trust. The Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre. 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 multifocal 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. Publisher PDF
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- 2015
24. Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer
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Nangalia, Jyoti, Gerstung, Moritz, Alexandrov, Ludmil B, Davies, Helen R, Teague, Jon W, Grundy, Richard, Shlien, Adam, Bolli, Niccolo, Unnikrishnan, Ashwin, Vassiliou, George S, Ju, Young Seok, Greaves, Mel, Green, Anthony R, Collins, V Peter, Gundem, Gunes, Behjati, Sam, Massie, Charles E, Santarius, Tom, Du, Ming-Qing, Pimanda, John E, Papaemmanuil, Elli, Munshi, Nikhil, Martincorena, Inigo, Teh, Bin Tean, Vyas, Paresh, Nik-Zainal, Serena, El-Naggar, Adel K, Hayes, D Neil, Taylor, Jack A, Ramakrishna, Manasa, Butler, Adam P, and Tarpey, Patrick S
- Abstract
Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication.
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- 2014
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25. HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer
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Ross-Adams, Helen, primary, Ball, Stephen, additional, Lawrenson, Kate, additional, Halim, Silvia, additional, Russell, Roslin, additional, Wells, Claire, additional, Strand, Siri H., additional, Ørntoft, Torben F., additional, Larson, Melissa, additional, Armasu, Sebastian, additional, Massie, Charles E., additional, Asim, Mohammad, additional, Mortensen, Martin M., additional, Borre, Michael, additional, Woodfine, Kathryn, additional, Warren, Anne Y., additional, Lamb, Alastair D., additional, Kay, Jonathan, additional, Whitaker, Hayley, additional, Ramos-Montoya, Antonio, additional, Murrell, Adele, additional, Sørensen, Karina D., additional, Fridley, Brooke L., additional, Goode, Ellen L., additional, Gayther, Simon A., additional, Masters, John, additional, Neal, David E., additional, and Mills, Ian G., additional
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- 2016
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26. The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis
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Massie, Charles E, Lynch, Andy, Ramos-Montoya, Antonio, Boren, Joan, Stark, Rory, Fazli, Ladan, Warren, Anne, Scott, Helen, Madhu, Basetti, Sharma, Naomi, Bon, Helene, Zecchini, Vinny, Smith, Donna-Michelle, DeNicola, Gina M, Mathews, Nik, Osborne, Michelle, Hadfield, James, MacArthur, Stewart, Adryan, Boris, Lyons, Scott K, Brindle, Kevin M, Griffiths, John, Gleave, Martin E, Rennie, Paul S, Neal, David E, and Mills, Ian G
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Male ,Proteomics ,Carcinoma ,Prostatic Neoplasms ,Antineoplastic Agents ,DNA ,Genomics ,Models, Biological ,Article ,DNA-Binding Proteins ,Systems Integration ,Metabolism ,Receptors, Androgen ,Cell Line, Tumor ,Data Interpretation, Statistical ,Drug Discovery ,Humans ,Molecular Targeted Therapy ,Protein Binding - Abstract
Using a combination of genomic and metabolomic profiling strategies, the CAMKK2 kinase is identified as a critical downstream target of the androgen receptor. CAMKK2 regulates anabolic flux, and represents an attractive therapeutic target for prostate cancer treatments.
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- 2011
27. Epigenetic and oncogenic regulation of SLC16A7 (MCT2) results in protein over-expression, impacting on signalling and cellular phenotypes in prostate cancer
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Pertega-Gomes, Nelma, primary, Vizcaino, Jose R., additional, Felisbino, Sergio, additional, Warren, Anne Y., additional, Shaw, Greg, additional, Kay, Jonathan, additional, Whitaker, Hayley, additional, Lynch, Andy G., additional, Fryer, Lee, additional, Neal, David E., additional, and Massie, Charles E., additional
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- 2015
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28. HES5 silencing is an early and recurrent change in prostate tumourigenesis
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Massie, Charles E, primary, Spiteri, Inmaculada, additional, Ross-Adams, Helen, additional, Luxton, Hayley, additional, Kay, Jonathan, additional, Whitaker, Hayley C, additional, Dunning, Mark J, additional, Lamb, Alastair D, additional, Ramos-Montoya, Antonio, additional, Brewer, Daniel S, additional, Cooper, Colin S, additional, Eeles, Rosalind, additional, _, _, additional, Warren, Anne Y, additional, Tavaré, Simon, additional, Neal, David E, additional, and Lynch, Andy G, additional
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- 2015
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29. The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis
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Massie, Charles E, primary, Lynch, Andy, additional, Ramos-Montoya, Antonio, additional, Boren, Joan, additional, Stark, Rory, additional, Fazli, Ladan, additional, Warren, Anne, additional, Scott, Helen, additional, Madhu, Basetti, additional, Sharma, Naomi, additional, Bon, Helene, additional, Zecchini, Vinny, additional, Smith, Donna-Michelle, additional, DeNicola, Gina M, additional, Mathews, Nik, additional, Osborne, Michelle, additional, Hadfield, James, additional, MacArthur, Stewart, additional, Adryan, Boris, additional, Lyons, Scott K, additional, Brindle, Kevin M, additional, Griffiths, John, additional, Gleave, Martin E, additional, Rennie, Paul S, additional, Neal, David E, additional, and Mills, Ian G, additional
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- 2011
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30. ChIPping away at gene regulation
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Massie, Charles E, primary and Mills, Ian G, additional
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- 2008
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31. New androgen receptor genomic targets show an interaction with the ETS1 transcription factor
- Author
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Massie, Charles E, primary, Adryan, Boris, additional, Barbosa‐Morais, Nuno L, additional, Lynch, Andy G, additional, Tran, Maxine G, additional, Neal, David E, additional, and Mills, Ian G, additional
- Published
- 2007
- Full Text
- View/download PDF
32. Mapping Protein–DNA Interactions Using ChIP-Sequencing.
- Author
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Massie, Charles E. and Mills, Ian G.
- Published
- 2012
- Full Text
- View/download PDF
33. OPCML at 11q25 is epigenetically inactivated and has tumor-suppressor function in epithelial ovarian cancer
- Author
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Sellar, Grant C, primary, Watt, Karen P, additional, Rabiasz, Genevieve J, additional, Stronach, Euan A, additional, Li, Li, additional, Miller, Eric P, additional, Massie, Charles E, additional, Miller, Jayne, additional, Contreras-Moreira, Bruno, additional, Scott, Diane, additional, Brown, Iain, additional, Williams, Alastair R, additional, Bates, Paul A, additional, Smyth, John F, additional, and Gabra, Hani, additional
- Published
- 2003
- Full Text
- View/download PDF
34. Inactivating CUX1 mutations promote tumorigenesis.
- Author
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Wong, Chi C, Martincorena, Inigo, Rust, Alistair G, Rashid, Mamunur, Alifrangis, Constantine, Alexandrov, Ludmil B, Tiffen, Jessamy C, Kober, Christina, Green, Anthony R, Massie, Charles E, Nangalia, Jyoti, Lempidaki, Stella, Döhner, Hartmut, Döhner, Konstanze, Bray, Sarah J, McDermott, Ultan, Papaemmanuil, Elli, Campbell, Peter J, and Adams, David J
- Subjects
GENE silencing ,GENETIC mutation ,NEOPLASTIC cell transformation ,CANCER genetics ,HOMEOBOX proteins ,GENETIC transcription - Abstract
A major challenge in cancer genetics is to determine which low-frequency somatic mutations are drivers of tumorigenesis. Here we interrogate the genomes of 7,651 diverse human cancers and find inactivating mutations in the homeodomain transcription factor gene CUX1 (cut-like homeobox 1) in ∼1-5% of various tumors. Meta-analysis of CUX1 mutational status in 2,519 cases of myeloid malignancies reveals disruptive mutations associated with poor survival, highlighting the clinical significance of CUX1 loss. In parallel, we validate CUX1 as a bona fide tumor suppressor using mouse transposon-mediated insertional mutagenesis and Drosophila cancer models. We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition. Thus, our complementary approaches identify CUX1 as a pan-driver of tumorigenesis and uncover a potential strategy for treating CUX1-mutant tumors. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
35. Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer
- Author
-
Ju, Young Seok, Alexandrov, Ludmil B, Gerstung, Moritz, Martincorena, Inigo, Nik-Zainal, Serena, Ramakrishna, Manasa, Davies, Helen R, Papaemmanuil, Elli, Gundem, Gunes, Shlien, Adam, Bolli, Niccolo, Behjati, Sam, Tarpey, Patrick S, Nangalia, Jyoti, Massie, Charles E, Butler, Adam P, Teague, Jon W, Vassiliou, George S, Green, Anthony R, Du, Ming-Qing, Unnikrishnan, Ashwin, Pimanda, John E, Teh, Bin Tean, Munshi, Nikhil, Greaves, Mel, Vyas, Paresh, El-Naggar, Adel K, Santarius, Tom, Collins, V Peter, Grundy, Richard, Taylor, Jack A, Hayes, D Neil, Malkin, David, ICGC Breast Cancer Group, ICGC Chronic Myeloid Disorders Group, ICGC Prostate Cancer Group, Foster, Christopher S, Warren, Anne Y, Whitaker, Hayley C, Brewer, Daniel, Eeles, Rosalind, Cooper, Colin, Neal, David, Visakorpi, Tapio, Isaacs, William B, Bova, G Steven, Flanagan, Adrienne M, Futreal, P Andrew, Lynch, Andy G, Chinnery, Patrick F, McDermott, Ultan, Stratton, Michael R, and Campbell, Peter J
- Subjects
DNA Replication ,Base Composition ,evolutionary biology ,High-Throughput Nucleotide Sequencing ,mitochondrial DNA ,mutational signature ,sequencing ,DNA ,DNA, Neoplasm ,DNA, Mitochondrial ,Polymorphism, Single Nucleotide ,3. Good health ,Mitochondria ,Evolution, Molecular ,Neoplasms ,cancer genome ,evolution ,Genome, Mitochondrial ,Mutation ,genomics ,Animals ,Data Mining ,Humans ,somatic mutation ,human - Abstract
Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication.
36. Comprehensive characterization of cell-free tumor DNA in plasma and urine of patients with renal tumors
- Author
-
Smith, Christopher G., Moser, Tina, Mouliere, Florent, Field-Rayner, Johanna, Eldridge, Matthew, Riediger, Anja L., Chandrananda, Dineika, Heider, Katrin, Wan, Jonathan C. M., Warren, Anne Y., Morris, James, Hudecova, Irena, Cooper, Wendy N., Mitchell, Thomas J., Gale, Davina, Ruiz-Valdepenas, Andrea, Klatte, Tobias, Ursprung, Stephan, Sala, Evis, Riddick, Antony C. P., Aho, Tevita F., Armitage, James N., Perakis, Samantha, Pichler, Martin, Seles, Maximilian, Wcislo, Gabriel, Welsh, Sarah J., Matakidou, Athena, Eisen, Tim, Massie, Charles E., Rosenfeld, Nitzan, Heitzer, Ellen, and Stewart, Grant D.
- Subjects
Predictive biomarker ,Renal cancer ,Research ,Heterogeneity ,Cell-free tumor DNA (ctDNA) ,3. Good health ,Personalized analysis - Abstract
Background: Cell-free tumor-derived DNA (ctDNA) allows non-invasive monitoring of cancers, but its utility in renal cell cancer (RCC) has not been established. Methods: Here, a combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n = 91) with various renal tumor subtypes, were used to determine ctDNA content in plasma and urine. Results: Our data revealed lower plasma ctDNA levels in RCC relative to other cancers of similar size and stage, with untargeted detection in 27.5% of patients from both cohorts. A sensitive personalized approach, applied to plasma and urine from select patients (n = 22) improved detection to ~ 50%, including in patients with early-stage disease and even benign lesions. Detection in plasma, but not urine, was more frequent amongst patients with larger tumors and in those patients with venous tumor thrombus. With data from one extensively characterized patient, we observed that plasma and, for the first time, urine ctDNA may better represent tumor heterogeneity than a single tissue biopsy. Furthermore, in a subset of patients (n = 16), longitudinal sampling revealed that ctDNA can track disease course and may pre-empt radiological identification of minimal residual disease or disease progression on systemic therapy. Additional datasets will be required to validate these findings. Conclusions: These data highlight RCC as a ctDNA-low malignancy. The biological reasons for this are yet to be determined. Nonetheless, our findings indicate potential clinical utility in the management of patients with renal tumors, provided improvement in isolation and detection approaches.
37. Comprehensive characterization of cell-free tumor DNA in plasma and urine of patients with renal tumors
- Author
-
Smith, Christopher G, Moser, Tina, Mouliere, Florent, Field-Rayner, Johanna, Eldridge, Matthew, Riediger, Anja L, Chandrananda, Dineika, Heider, Katrin, Wan, Jonathan CM, Warren, Anne Y, Morris, James, Hudecova, Irena, Cooper, Wendy N, Mitchell, Thomas J, Gale, Davina, Ruiz-Valdepenas, Andrea, Klatte, Tobias, Ursprung, Stephan, Sala, Evis, Riddick, Antony CP, Aho, Tevita F, Armitage, James N, Perakis, Samantha, Pichler, Martin, Seles, Maximilian, Wcislo, Gabriel, Welsh, Sarah J, Matakidou, Athena, Eisen, Tim, Massie, Charles E, Rosenfeld, Nitzan, Heitzer, Ellen, and Stewart, Grant D
- Subjects
Aged, 80 and over ,Male ,Whole Genome Sequencing ,Middle Aged ,Kidney Neoplasms ,3. Good health ,Personalized analysis ,Circulating Tumor DNA ,Predictive biomarker ,Genetic Heterogeneity ,Renal cancer ,Biomarkers, Tumor ,Humans ,Female ,Heterogeneity ,Cell-free tumor DNA (ctDNA) ,Aged - Abstract
BACKGROUND: Cell-free tumor-derived DNA (ctDNA) allows non-invasive monitoring of cancers, but its utility in renal cell cancer (RCC) has not been established. METHODS: Here, a combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n = 91) with various renal tumor subtypes, were used to determine ctDNA content in plasma and urine. RESULTS: Our data revealed lower plasma ctDNA levels in RCC relative to other cancers of similar size and stage, with untargeted detection in 27.5% of patients from both cohorts. A sensitive personalized approach, applied to plasma and urine from select patients (n = 22) improved detection to ~ 50%, including in patients with early-stage disease and even benign lesions. Detection in plasma, but not urine, was more frequent amongst patients with larger tumors and in those patients with venous tumor thrombus. With data from one extensively characterized patient, we observed that plasma and, for the first time, urine ctDNA may better represent tumor heterogeneity than a single tissue biopsy. Furthermore, in a subset of patients (n = 16), longitudinal sampling revealed that ctDNA can track disease course and may pre-empt radiological identification of minimal residual disease or disease progression on systemic therapy. Additional datasets will be required to validate these findings. CONCLUSIONS: These data highlight RCC as a ctDNA-low malignancy. The biological reasons for this are yet to be determined. Nonetheless, our findings indicate potential clinical utility in the management of patients with renal tumors, provided improvement in isolation and detection approaches.
38. Comprehensive characterization of cell-free tumor DNA in plasma and urine of patients with renal tumors
- Author
-
Smith, Christopher G., Moser, Tina, Mouliere, Florent, Field-Rayner, Johanna, Eldridge, Matthew, Riediger, Anja L., Chandrananda, Dineika, Heider, Katrin, Wan, Jonathan C. M., Warren, Anne Y., Morris, James, Hudecova, Irena, Cooper, Wendy N., Mitchell, Thomas J., Gale, Davina, Ruiz-Valdepenas, Andrea, Klatte, Tobias, Ursprung, Stephan, Sala, Evis, Riddick, Antony C. P., Aho, Tevita F., Armitage, James N., Perakis, Samantha, Pichler, Martin, Seles, Maximilian, Wcislo, Gabriel, Welsh, Sarah J., Matakidou, Athena, Eisen, Tim, Massie, Charles E., Rosenfeld, Nitzan, Heitzer, Ellen, and Stewart, Grant D.
- Subjects
Predictive biomarker ,Renal cancer ,Research ,Heterogeneity ,Cell-free tumor DNA (ctDNA) ,3. Good health ,Personalized analysis - Abstract
Background: Cell-free tumor-derived DNA (ctDNA) allows non-invasive monitoring of cancers, but its utility in renal cell cancer (RCC) has not been established. Methods: Here, a combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n = 91) with various renal tumor subtypes, were used to determine ctDNA content in plasma and urine. Results: Our data revealed lower plasma ctDNA levels in RCC relative to other cancers of similar size and stage, with untargeted detection in 27.5% of patients from both cohorts. A sensitive personalized approach, applied to plasma and urine from select patients (n = 22) improved detection to ~ 50%, including in patients with early-stage disease and even benign lesions. Detection in plasma, but not urine, was more frequent amongst patients with larger tumors and in those patients with venous tumor thrombus. With data from one extensively characterized patient, we observed that plasma and, for the first time, urine ctDNA may better represent tumor heterogeneity than a single tissue biopsy. Furthermore, in a subset of patients (n = 16), longitudinal sampling revealed that ctDNA can track disease course and may pre-empt radiological identification of minimal residual disease or disease progression on systemic therapy. Additional datasets will be required to validate these findings. Conclusions: These data highlight RCC as a ctDNA-low malignancy. The biological reasons for this are yet to be determined. Nonetheless, our findings indicate potential clinical utility in the management of patients with renal tumors, provided improvement in isolation and detection approaches.
39. Measurement of Plasma Cell-Free Mitochondrial Tumor DNA Improves Detection of Glioblastoma in Patient-Derived Orthotopic Xenograft Models
- Author
-
Mair, Richard, Mouliere, Florent, Smith, Christopher G, Chandrananda, Dineika, Gale, Davina, Marass, Francesco, Tsui, Dana WY, Massie, Charles E, Wright, Alan J, Watts, Colin, Rosenfeld, Nitzan, and Brindle, Kevin M
- Subjects
High-Throughput Nucleotide Sequencing ,DNA, Neoplasm ,DNA, Mitochondrial ,Xenograft Model Antitumor Assays ,3. Good health ,Body Fluids ,Circulating Tumor DNA ,Mitochondria ,Rats ,Rats, Nude ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Animals ,Humans ,Female ,Glioblastoma - Abstract
The factors responsible for the low detection rate of cell-free tumor DNA (ctDNA) in the plasma of patients with glioblastoma (GBM) are currently unknown. In this study, we measured circulating nucleic acids in patient-derived orthotopically implanted xenograft (PDOX) models of GBM (n = 64) and show that tumor size and cell proliferation, but not the integrity of the blood-brain barrier or cell death, affect the release of ctDNA in treatment-naïve GBM PDOX. Analysis of fragment length profiles by shallow genome-wide sequencing (
40. Comprehensive characterization of cell-free tumor DNA in plasma and urine of patients with renal tumors
- Author
-
Smith, Christopher G, Moser, Tina, Mouliere, Florent, Field-Rayner, Johanna, Eldridge, Matthew, Riediger, Anja L, Chandrananda, Dineika, Heider, Katrin, Wan, Jonathan C M, Warren, Anne Y, Morris, James, Hudecova, Irena, Cooper, Wendy N, Mitchell, Thomas J, Gale, Davina, Ruiz-Valdepenas, Andrea, Klatte, Tobias, Ursprung, Stephan, Sala, Evis, Riddick, Antony C P, Aho, Tevita F, Armitage, James N, Perakis, Samantha, Pichler, Martin, Seles, Maximilian, Wcislo, Gabriel, Welsh, Sarah J, Matakidou, Athena, Eisen, Tim, Massie, Charles E, Rosenfeld, Nitzan, Heitzer, Ellen, and Stewart, Grant D
- Subjects
Renal Cancer ,Personalized Analysis ,Predictive Biomarker ,Cell-free Tumor Dna (Ctdna) ,Heterogeneity ,3. Good health - Abstract
BACKGROUND:Cell-free tumor-derived DNA (ctDNA) allows non-invasive monitoring of cancers, but its utility in renal cell cancer (RCC) has not been established. METHODS:Here, a combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n = 91) with various renal tumor subtypes, were used to determine ctDNA content in plasma and urine. RESULTS:Our data revealed lower plasma ctDNA levels in RCC relative to other cancers of similar size and stage, with untargeted detection in 27.5% of patients from both cohorts. A sensitive personalized approach, applied to plasma and urine from select patients (n = 22) improved detection to ~ 50%, including in patients with early-stage disease and even benign lesions. Detection in plasma, but not urine, was more frequent amongst patients with larger tumors and in those patients with venous tumor thrombus. With data from one extensively characterized patient, we observed that plasma and, for the first time, urine ctDNA may better represent tumor heterogeneity than a single tissue biopsy. Furthermore, in a subset of patients (n = 16), longitudinal sampling revealed that ctDNA can track disease course and may pre-empt radiological identification of minimal residual disease or disease progression on systemic therapy. Additional datasets will be required to validate these findings. CONCLUSIONS:These data highlight RCC as a ctDNA-low malignancy. The biological reasons for this are yet to be determined. Nonetheless, our findings indicate potential clinical utility in the management of patients with renal tumors, provided improvement in isolation and detection approaches.
41. Enhanced detection of circulating tumor DNA by fragment size analysis
- Author
-
Nitzan Rosenfeld, Christopher Smith, Charles E. Massie, Florent Mouliere, Ioannis Gounaris, Irena Hudecova, Lise Barlebo Ahlborn, Kevin M. Brindle, Christine Parkinson, Grant D. Stewart, Francesco Marass, Pippa Corrie, Richard D. Baird, Mercedes Jimenez-Linan, Dineika Chandrananda, James D. Brenton, Suzanne Murphy, Wendy N. Cooper, Johanna Burge, Matthew D. Eldridge, Anna Supernat, Olga Østrup, Morten Mau-Sørensen, Javier Garcia-Corbacho, Keval M. Patel, Elizabeth Moore, Davina Gale, James Morris, Simon Pacey, Michiel S. van der Heijden, Anna M. Piskorz, Katrin Heider, Jonathan C. M. Wan, Colin Watts, Richard Mair, Susana Ros, Teodora Goranova, Pathology, Mouliere, Florent [0000-0001-7043-0514], Chandrananda, Dineika [0000-0002-8834-9500], Piskorz, Anna M [0000-0002-7171-1120], Moore, Elizabeth K [0000-0002-2728-3202], Goranova, Teodora [0000-0003-3848-2968], Marass, Francesco [0000-0002-8993-7320], Heider, Katrin [0000-0003-4035-1668], Wan, Jonathan CM [0000-0003-0001-1802], Hudecova, Irena [0000-0003-3823-9896], Eldridge, Matthew D [0000-0002-5799-8911], Gale, Davina [0000-0002-4521-8199], Stewart, Grant D [0000-0003-3188-9140], Cooper, Wendy N [0000-0003-3416-9982], Massie, Charles E [0000-0003-2314-4843], Watts, Colin [0000-0003-3531-8791], Corrie, Pippa [0000-0003-4875-7021], Brindle, Kevin M [0000-0003-3883-6287], Baird, Richard D [0000-0001-7071-6483], Mau-Sørensen, Morten [0000-0003-2235-1250], Smith, Christopher G [0000-0001-7357-2737], Brenton, James D [0000-0002-5738-6683], Rosenfeld, Nitzan [0000-0002-2825-4788], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,DNA Copy Number Variations ,In silico ,Copy number analysis ,Biology ,medicine.disease_cause ,Deep sequencing ,Circulating Tumor DNA ,Machine Learning ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,medicine ,Animals ,Humans ,Whole genome sequencing ,Mutation ,Whole Genome Sequencing ,Genome, Human ,Cancer ,General Medicine ,medicine.disease ,Molecular biology ,030104 developmental biology ,chemistry ,Human genome ,DNA - Abstract
Existing methods to improve detection of circulating tumor DNA (ctDNA) have focused on genomic alterations but have rarely considered the biological properties of plasma cell-free DNA (cfDNA). We hypothesized that differences in fragment lengths of circulating DNA could be exploited to enhance sensitivity for detecting the presence of ctDNA and for noninvasive genomic analysis of cancer. We surveyed ctDNA fragment sizes in 344 plasma samples from 200 patients with cancer using low-pass whole-genome sequencing (0.4×). To establish the size distribution of mutant ctDNA, tumor-guided personalized deep sequencing was performed in 19 patients. We detected enrichment of ctDNA in fragment sizes between 90 and 150 bp and developed methods for in vitro and in silico size selection of these fragments. Selecting fragments between 90 and 150 bp improved detection of tumor DNA, with more than twofold median enrichment in >95% of cases and more than fourfold enrichment in >10% of cases. Analysis of size-selected cfDNA identified clinically actionable mutations and copy number alterations that were otherwise not detected. Identification of plasma samples from patients with advanced cancer was improved by predictive models integrating fragment length and copy number analysis of cfDNA, with area under the curve (AUC) >0.99 compared to AUC 0.91 compared to AUC < 0.5 without fragmentation features. Fragment size analysis and selective sequencing of specific fragment sizes can boost ctDNA detection and could complement or provide an alternative to deeper sequencing of cfDNA.
- Published
- 2018
- Full Text
- View/download PDF
42. Measurement of Plasma Cell-Free Mitochondrial Tumor DNA Improves Detection of Glioblastoma in Patient-Derived Orthotopic Xenograft Models
- Author
-
Florent Mouliere, Charles E. Massie, Nitzan Rosenfeld, Colin Watts, Christopher Smith, Dineika Chandrananda, Francesco Marass, Richard Mair, Davina Gale, Dana W.Y. Tsui, Kevin M. Brindle, Alan J. Wright, Pathology, CCA - Cancer biology and immunology, Chandrananda, Dineika [0000-0002-8834-9500], Marass, Francesco [0000-0002-8993-7320], Massie, Charles E [0000-0003-2314-4843], Wright, Alan J [0000-0002-4577-5681], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Cancer Research ,Mitochondrial DNA ,Plasma cell ,Mitochondrion ,DNA, Mitochondrial ,Article ,Circulating Tumor DNA ,03 medical and health sciences ,chemistry.chemical_compound ,Rats, Nude ,0302 clinical medicine ,Glioma ,medicine ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Animals ,Humans ,Digital polymerase chain reaction ,Temozolomide ,Cell growth ,High-Throughput Nucleotide Sequencing ,DNA, Neoplasm ,medicine.disease ,Xenograft Model Antitumor Assays ,3. Good health ,Body Fluids ,Mitochondria ,Rats ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Glioblastoma ,DNA ,medicine.drug - Abstract
The factors responsible for the low detection rate of cell-free tumor DNA (ctDNA) in the plasma of patients with glioblastoma (GBM) are currently unknown. In this study, we measured circulating nucleic acids in patient-derived orthotopically implanted xenograft (PDOX) models of GBM (n = 64) and show that tumor size and cell proliferation, but not the integrity of the blood–brain barrier or cell death, affect the release of ctDNA in treatment-naïve GBM PDOX. Analysis of fragment length profiles by shallow genome-wide sequencing ( Significance: These findings show that detection of tumor mitochondrial DNA is more sensitive than circulating tumor DNA analysis to detect and monitor tumor burden in patient-derived orthotopic xenografts of glioblastoma.
- Published
- 2018
43. Methods to Identify Chromatin-Bound Protein Complexes: From Genome-Wide to Locus-Specific Approaches.
- Author
-
Massie CE
- Subjects
- High-Throughput Nucleotide Sequencing methods, Humans, Male, Prostatic Neoplasms genetics, Proteomics methods, Sequence Analysis, DNA methods, Tumor Cells, Cultured, Chromatin metabolism, Chromatin Immunoprecipitation methods, Genetic Loci, Genome, Human, Prostatic Neoplasms metabolism, Receptors, Androgen metabolism
- Abstract
High-throughput sequencing approaches coupled with functional genomics experiments have facilitated a rapid growth in our understanding of chromatin biology, from genome-wide maps of transcription factor binding and histone modifications to insights into higher order chromatin organization under specific cellular conditions. However in most cases these methods require a prior knowledge of the system of interest (e.g., targets for immunoprecipitation or modulation) and therefore are limited in their utility to identify novel components of pathways or for the study of uncharacterized pathways. Several orthologous proteomics approaches have been developed recently that bridge this gap, allowing the identification of protein complexes globally or at specific genomic loci. In this chapter the relative advantages of each approach will be explored and a detailed protocol given for DNA pull-down of a specific androgen receptor (AR) genomic target.
- Published
- 2016
- Full Text
- View/download PDF
44. STAT1 activation in association with JAK2 exon 12 mutations.
- Author
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Godfrey AL, Chen E, Massie CE, Silber Y, Pagano F, Bellosillo B, Guglielmelli P, Harrison CN, Reilly JT, Stegelmann F, Bijou F, Lippert E, Boiron JM, Döhner K, Vannucchi AM, Besses C, and Green AR
- Subjects
- Adult, Aged, Aged, 80 and over, Amino Acid Substitution, Female, Humans, Male, Middle Aged, Exons, Janus Kinase 2 genetics, Janus Kinase 2 metabolism, Mutation, Missense, STAT1 Transcription Factor genetics, STAT1 Transcription Factor metabolism, Thrombocythemia, Essential genetics, Thrombocythemia, Essential metabolism, Thrombocythemia, Essential pathology
- Published
- 2016
- Full Text
- View/download PDF
45. Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target.
- Author
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Asim M, Massie CE, Orafidiya F, Pértega-Gomes N, Warren AY, Esmaeili M, Selth LA, Zecchini HI, Luko K, Qureshi A, Baridi A, Menon S, Madhu B, Escriu C, Lyons S, Vowler SL, Zecchini VR, Shaw G, Hessenkemper W, Russell R, Mohammed H, Stefanos N, Lynch AG, Grigorenko E, D'Santos C, Taylor C, Lamb A, Sriranjan R, Yang J, Stark R, Dehm SM, Rennie PS, Carroll JS, Griffiths JR, Tavaré S, Mills IG, McEwan IJ, Baniahmad A, Tilley WD, and Neal DE
- Subjects
- Aged, Animals, Choline Kinase antagonists & inhibitors, Choline Kinase genetics, Enzyme Inhibitors pharmacology, Gene Expression Regulation, Neoplastic, Humans, Kaplan-Meier Estimate, Male, Mice, Mice, Inbred NOD, Mice, SCID, Middle Aged, Neoplasm Grading, Neoplasm Staging, Proportional Hazards Models, Prostatic Neoplasms pathology, Prostatic Neoplasms surgery, Sequence Analysis, DNA, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Biomarkers, Tumor metabolism, Choline Kinase metabolism, Molecular Chaperones, Molecular Targeted Therapy methods, Prostatectomy methods, Prostatic Neoplasms drug therapy, Prostatic Neoplasms enzymology, Receptors, Androgen metabolism, Signal Transduction
- Abstract
Background: The androgen receptor (AR) is a major drug target in prostate cancer (PCa). We profiled the AR-regulated kinome to identify clinically relevant and druggable effectors of AR signaling., Methods: Using genome-wide approaches, we interrogated all AR regulated kinases. Among these, choline kinase alpha (CHKA) expression was evaluated in benign (n = 195), prostatic intraepithelial neoplasia (PIN) (n = 153) and prostate cancer (PCa) lesions (n = 359). We interrogated how CHKA regulates AR signaling using biochemical assays and investigated androgen regulation of CHKA expression in men with PCa, both untreated (n = 20) and treated with an androgen biosynthesis inhibitor degarelix (n = 27). We studied the effect of CHKA inhibition on the PCa transcriptome using RNA sequencing and tested the effect of CHKA inhibition on cell growth, clonogenic survival and invasion. Tumor xenografts (n = 6 per group) were generated in mice using genetically engineered prostate cancer cells with inducible CHKA knockdown. Data were analyzed with χ(2) tests, Cox regression analysis, and Kaplan-Meier methods. All statistical tests were two-sided., Results: CHKA expression was shown to be androgen regulated in cell lines, xenografts, and human tissue (log fold change from 6.75 to 6.59, P = .002) and was positively associated with tumor stage. CHKA binds directly to the ligand-binding domain (LBD) of AR, enhancing its stability. As such, CHKA is the first kinase identified as an AR chaperone. Inhibition of CHKA repressed the AR transcriptional program including pathways enriched for regulation of protein folding, decreased AR protein levels, and inhibited the growth of PCa cell lines, human PCa explants, and tumor xenografts., Conclusions: CHKA can act as an AR chaperone, providing, to our knowledge, the first evidence for kinases as molecular chaperones, making CHKA both a marker of tumor progression and a potential therapeutic target for PCa., (© The Author 2015. Published by Oxford University Press.)
- Published
- 2015
- Full Text
- View/download PDF
46. Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer.
- Author
-
Ju YS, Alexandrov LB, Gerstung M, Martincorena I, Nik-Zainal S, Ramakrishna M, Davies HR, Papaemmanuil E, Gundem G, Shlien A, Bolli N, Behjati S, Tarpey PS, Nangalia J, Massie CE, Butler AP, Teague JW, Vassiliou GS, Green AR, Du MQ, Unnikrishnan A, Pimanda JE, Teh BT, Munshi N, Greaves M, Vyas P, El-Naggar AK, Santarius T, Collins VP, Grundy R, Taylor JA, Hayes DN, Malkin D, Foster CS, Warren AY, Whitaker HC, Brewer D, Eeles R, Cooper C, Neal D, Visakorpi T, Isaacs WB, Bova GS, Flanagan AM, Futreal PA, Lynch AG, Chinnery PF, McDermott U, Stratton MR, and Campbell PJ
- Subjects
- Animals, Base Composition, DNA Replication, Data Mining, Evolution, Molecular, High-Throughput Nucleotide Sequencing, Humans, Mitochondria genetics, Mitochondria pathology, Neoplasms classification, Neoplasms pathology, Polymorphism, Single Nucleotide, DNA genetics, DNA, Mitochondrial genetics, DNA, Neoplasm genetics, Genome, Mitochondrial, Mutation, Neoplasms genetics
- Abstract
Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication.
- Published
- 2014
- Full Text
- View/download PDF
47. Mapping protein-DNA interactions using ChIP-sequencing.
- Author
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Massie CE and Mills IG
- Subjects
- Animals, Humans, Protein Binding, Protein Interaction Mapping, Receptors, Androgen metabolism, Receptors, Cytoplasmic and Nuclear metabolism, Chromatin Immunoprecipitation methods, DNA metabolism, High-Throughput Nucleotide Sequencing methods
- Abstract
Chromatin immunoprecipitation (ChIP) allows enrichment of genomic regions which are associated with specific transcription factors, histone modifications, and indeed any other epitopes which are present on chromatin. The original ChIP methods used site-specific PCR and Southern blotting to confirm which regions of the genome were enriched, on a candidate basis. The combination of ChIP with genomic tiling arrays (ChIP-chip) allowed a more unbiased approach to map ChIP-enriched sites. However, limitations of microarray probe design and probe number have a detrimental impact on the coverage, resolution, sensitivity, and cost of whole-genome tiling microarray sets for higher eukaryotes with large genomes. The combination of ChIP with high-throughput sequencing technology has allowed more comprehensive surveys of genome occupancy, greater resolution, and lower cost for whole genome coverage. Herein, we provide a comparison of high-throughput sequencing platforms and a survey of ChIP-seq analysis tools, discuss experimental design, and describe a detailed ChIP-seq method.Chromatin immunoprecipitation (ChIP) allows enrichment of genomic regions which are associated with specific transcription factors, histone modifications, and indeed any other epitopes which are present on chromatin. The original ChIP methods used site-specific PCR and Southern blotting to confirm which regions of the genome were enriched, on a candidate basis. The combination of ChIP with genomic tiling arrays (ChIP-chip) allowed a more unbiased approach to map ChIP-enriched sites. However, limitations of microarray probe design and probe number have a detrimental impact on the coverage, resolution, sensitivity, and cost of whole-genome tiling microarray sets for higher eukaryotes with large genomes. The combination of ChIP with high-throughput sequencing technology has allowed more comprehensive surveys of genome occupancy, greater resolution, and lower cost for whole genome coverage. Herein, we provide a comparison of high-throughput sequencing platforms and a survey of ChIP-seq analysis tools, discuss experimental design, and describe a detailed ChIP-seq method.
- Published
- 2012
- Full Text
- View/download PDF
48. Global identification of androgen response elements.
- Author
-
Massie CE and Mills IG
- Subjects
- Cell Culture Techniques, Cell Line, Tumor, Chromatin Immunoprecipitation, Humans, Oligonucleotide Array Sequence Analysis, Androgens physiology, Receptors, Androgen metabolism, Response Elements genetics
- Abstract
Chromatin immunoprecipitation (ChIP) is an invaluable tool in the study of transcriptional regulation. ChIP methods require both a priori knowledge of the transcriptional regulators which are important for a given biological system and high-quality specific antibodies for these targets. The androgen receptor (AR) is known to play essential roles in male sexual development, in prostate cancer and in the function of many other AR-expressing cell types (e.g. neurons and myocytes). As a ligand-activated transcription factor the AR also represents an endogenous, inducible system to study transcriptional biology. Therefore, ChIP studies of the AR can make use of treatment contrast experiments to define its transcriptional targets. To date several studies have mapped AR binding sites using ChIP in combination with genome tiling microarrays (ChIP-chip) or direct sequencing (ChIP-seq), mainly in prostate cancer cell lines and with varying degrees of genomic coverage. These studies have provided new insights into the DNA sequences to which the AR can bind, identified AR cooperating transcription factors, mapped thousands of potential AR regulated genes and provided insights into the biological processes regulated by the AR. However, further ChIP studies will be required to fully characterise the dynamics of the AR-regulated transcriptional programme, to map the occupancy of different AR transcriptional complexes which result in different transcriptional output and to delineate the transcriptional networks downstream of the AR.
- Published
- 2011
- Full Text
- View/download PDF
49. Chromatin immunoprecipitation (ChIP) methodology and readouts.
- Author
-
Massie CE and Mills IG
- Subjects
- Cell Line, Tumor, Chromatin Immunoprecipitation instrumentation, Gene Expression Profiling instrumentation, Gene Expression Profiling methods, Humans, Microarray Analysis instrumentation, Microarray Analysis methods, Polymerase Chain Reaction methods, Chromatin Immunoprecipitation methods
- Abstract
The identification of direct nuclear hormone receptor gene targets provides clues to their contribution to both development and cancer progression. Until recently, the identification of such direct target genes has relied on a combination of expression analysis and in silico searches for consensus binding motifs in gene promoters. Consensus binding motifs for transcription factors are often defined using in vitro DNA binding strategies. Such in vitro strategies fail to account for the many factors that contribute significantly to target selection by transcription factors in cells beyond the recognition of these short consensus DNA sequences. These factors include DNA methylation, chromatin structure, posttranslational modifications of transcription factors, and the cooperative recruitment of transcription factor complexes. Chromatin immunoprecipitation (ChIP) provides a means of isolating transcription factor complexes in the context of endogenous chromatin, allowing the identification of direct transcription factor targets. ChIP can be combined with site-specific PCR for candidate binding sites or alternatively with cloning, genomic microarrays or more recently direct high throughput sequencing to identify novel genomic targets. The application of ChIP-based approaches has redefined consensus binding motifs for transcription factors and provided important insights into transcription factor biology.
- Published
- 2009
- Full Text
- View/download PDF
50. Identification of clinically relevant genes on chromosome 11 in a functional model of ovarian cancer tumor suppression.
- Author
-
Stronach EA, Sellar GC, Blenkiron C, Rabiasz GJ, Taylor KJ, Miller EP, Massie CE, Al-Nafussi A, Smyth JF, Porteous DJ, and Gabra H
- Subjects
- Cell Division genetics, Cell Line, Tumor, Female, Gene Expression, Gene Transfer Techniques, Humans, Ovarian Neoplasms pathology, Reverse Transcriptase Polymerase Chain Reaction, Chromosomes, Human, Pair 11 genetics, Genes, Tumor Suppressor, Ovarian Neoplasms genetics
- Abstract
Microcell-mediated transfer of normal chromosome 11 (chr 11) to a clonal derivative of the ovarian cancer cell line, OVCAR3, was performed and generated independent hybrids with a common set of phenotypes: inhibition of cell growth and of cellular migration in vitro; and inhibition of tumor growth in vivo. Differential display reverse transcriptase-PCR (RT-PCR), cDNA-representational difference analysis, and hybridization of cDNA high-density filter arrays identified altered mRNAs associated with these phenotypic alterations. Quantitative RT-PCR-based validation of each altered mRNA eliminated false positives to identify a reduced set of expression differences. Twelve products were confirmed as up-regulated and 4 as down-regulated upon introduction of chr 11. Strikingly, 4 of the 12 up-regulated genes were located on chr 11. Expression analysis of selected products by quantitative RT-PCR in a series of 18 human primary ovarian tumors revealed several associations with clinicopathological features. Importantly, low expression of two products, the lysosomal protease CTSD and the lens crystallin CRYAB, was significantly associated with adverse patient survival. Immunohistochemical analysis of CTSD in a larger independent panel of 58 primary ovarian tumors confirmed that low CTSD was associated with poor survival. Furthermore, low CTSD was significantly associated with serous histology and advanced tumor stage. The combined approach of microcell-mediated chromosome transfer and expression difference analysis has identified several altered mRNAs in a model of chr 11-mediated ovarian tumor suppression. The detailed contextual characterization of these genes will determine the extent of their involvement in neoplastic development.
- Published
- 2003
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