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1. Multi-Omic Analysis of Esophageal Adenocarcinoma Uncovers Candidate Therapeutic Targets and Cancer-Selective Posttranscriptional Regulation

Author

Fitzgerald, Rebecca C., Edwards, Paul A.W., Grehan, Nicola, Nutzinger, Barbara, Loreno, Christine, Redmond, Aisling M., Abbas, Sujath, Freeman, Adam, Smyth, Elizabeth C., O'Donovan, Maria, Miremadi, Ahmad, Malhotra, Shalini, Tripathi, Monika, Cheah, Calvin, Coles, Hannah, Millington, Curtis, Devonshire, Ginny, Eldridge, Matthew, Secrier, Maria, Jammula, Sriganesh, Davies, Jim, Crichton, Charles, Carroll, Nick, Hardwick, Richard H., Safranek, Peter, Hindmarsh, Andrew, Sujendran, Vijayendran, Hayes, Stephen J., Ang, Yeng, Sharrocks, Andrew, Preston, Shaun R., Bagwan, Izhar, Save, Vicki, Skipworth, Richard J.E., Hupp, Ted R., O'Neill, J Robert, Tucker, Olga, Beggs, Andrew, Taniere, Philippe, Puig, Sonia, Contino, Gianmarco, Underwood, Timothy J., Walker, Robert C., Grace, Ben L., Lagergren, Jesper, Gossage, James, Davies, Andrew, Chang, Fuju, Mahadeva, Ula, Goh, Vicky, Ciccarelli, Francesca D., Sanders, Grant, Berrisford, Richard, Chan, David, Cheong, Ed, Kumar, Bhaskar, Sreedharan, L., Parsons, Simon L., Soomro, Irshad, Kaye, Philip, Saunders, John, Lovat, Laurence, Haidry, Rehan, Scott, Michael, Sothi, Sharmila, Lishman, Suzy, Hanna, George B., Peters, Christopher J., Moorthy, Krishna, Grabowska, Anna, Turkington, Richard, McManus, Damian, Coleman, Helen, Petty, Russell D., Bartlet, Freddie, O'Neill, J. Robert, Yébenes Mayordomo, Marcos, Mitulović, Goran, Al Shboul, Sofian, Bedran, Georges, Faktor, Jakub, Hernychova, Lenka, Uhrik, Lukas, Gómez-Herranz, Maria, Kocikowski, Mikołaj, Vojtěšek, Bořivoj, Arends, Mark J., Hupp, Ted, and Alfaro, Javier Antonio

Published
2024
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4. Serial ctDNA detection using a personalized, tumor-informed assay in esophageal adenocarcinoma patients following resection

Author

Ococks, Emma, Sharma, Shruti, Tian Ng, Alvin Wei, Aleshin, Alexey, Fitzgerald, Rebecca C., Smyth, Elizabeth, Edwards, Paul A.W., Grehan, Nicola, Nutzinger, Barbara, Fidziukiewicz, Elwira, Redmond, Aisling M., Northrop, Alex, Abbas, Sujath, Smyth, Elizabeth C., O’Donovan, Maria, Miremadi, Ahmad, Malhotra, Shalini, Tripathi, Monika, Grantham, Amber, Cheah, Calvin, Coles, Hannah, Flint, Connor, Eldridge, Matthew, Secrier, Maria, Devonshire, Ginny, Jammula, Sriganesh, Davies, Jim, Crichton, Charles, Carroll, Nick, Hardwick, Richard H., Safranek, Peter, Hindmarsh, Andrew, Sujendran, Vijayendran, Hayes, Stephen J., Ang, Yeng, Sharrocks, Andrew, Preston, Shaun R., Bagwan, Izhar, Save, Vicki, Skipworth, Richard J.E., Hupp, Ted R., O’Neill, J. Robert, Tucker, Olga, Beggs, Andrew, Taniere, Philippe, Puig, Sonia, Contino, Gianmarco, Underwood, Timothy J., Walker, Robert C., Grace, Ben L., Lagergren, Jesper, Gossage, James, Davies, Andrew, Chang, Fuju, Mahadeva, Ula, Goh, Vicky, Ciccarelli, Francesca D., Sanders, Grant, Berrisford, Richard, Chan, David, Cheong, Ed, Kumar, Bhaskar, Sreedharan, L., Parsons, Simon L., Soomro, Irshad, Kaye, Philip, Saunders, John, Lovat, Laurence, Haidry, Rehan, Scott, Michael, Sothi, Sharmila, Lishman, Suzy, Hanna, George B., Peters, Christopher J., Moorthy, Krishna, Grabowska, Anna, Turkington, Richard, McManus, Damian, Coleman, Helen, and Petty, Russell D.

Published
2021
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7. Rearrangement processes and structural variations show evidence of selection in oesophageal adenocarcinomas

Author

Ng, Alvin Wei Tian, Contino, Gianmarco, Killcoyne, Sarah, Devonshire, Ginny, Hsu, Ray, Abbas, Sujath, Su, Jing, Redmond, Aisling M., Weaver, Jamie M.J., Eldridge, Matthew D., Tavaré, Simon, Grehan, Nicola, Nutzinger, Barbara, Fidziukiewicz, Elwira, Freeman, Adam, Smyth, Elizabeth C., O’Donovan, Maria, Miremadi, Ahmad, Malhotra, Shalini, Tripathi, Monika, Cheah, Calvin, Coles, Hannah, Flint, Connor, Eldridge, Matthew, Secrier, Maria, Jammula, Sriganesh, Davies, Jim, Crichton, Charles, Carroll, Nick, Hardwick, Richard H., Safranek, Peter, Hindmarsh, Andrew, Sujendran, Vijayendran, Hayes, Stephen J., Ang, Yeng, Sharrocks, Andrew, Preston, Shaun R., Bagwan, Izhar, Save, Vicki, Skipworth, Richard J.E., Hupp, Ted R., O’Neill, J. Robert, Tucker, Olga, Beggs, Andrew, Taniere, Philippe, Puig, Sonia, Scott, Michael, Turkington, Richard, McManus, Damian, Coleman, Helen, Ng, Alvin Wei Tian [0000-0003-4672-0815], Devonshire, Ginny [0000-0002-1408-8176], Eldridge, Matthew D [0000-0002-5799-8911], Edwards, Paul AW [0000-0002-4789-3374], Fitzgerald, Rebecca C [0000-0002-3434-3568], Apollo - University of Cambridge Repository, Eldridge, Matthew [0000-0002-5799-8911], and Fitzgerald, Rebecca [0000-0002-3434-3568]

Subjects
Esophageal Neoplasms, Whole Genome Sequencing, Agricultural and Biological Sciences(all), 631/67/1504/1477, 45, Genome, Human, Biochemistry, Genetics and Molecular Biology(all), article, Medicine (miscellaneous), 45/22, 45/23, 631/67/69, Adenocarcinoma, General Biochemistry, Genetics and Molecular Biology, 631/67/395, 631/67/1244, Humans, General Agricultural and Biological Sciences, Histone Acetyltransferases
Abstract

Oesophageal adenocarcinoma (OAC) provides an ideal case study to characterize large-scale rearrangements. Using whole genome short-read sequencing of 383 cases, for which 214 had matched whole transcriptomes, we observed structural variations (SV) with a predominance of deletions, tandem duplications and inter-chromosome junctions that could be identified as LINE-1 mobile element (ME) insertions. Complex clusters of rearrangements resembling breakage-fusion-bridge cycles or extrachromosomal circular DNA accounted for 22% of complex SVs affecting known oncogenes. Counting SV events affecting known driver genes substantially increased the recurrence rates of these drivers. After excluding fragile sites, we identified 51 candidate new drivers in genomic regions disrupted by SVs, including ETV5, KAT6B and CLTC. RUNX1 was the most recurrently altered gene (24%), with many deletions inactivating the RUNT domain but preserved the reading frame, suggesting an altered protein product. These findings underscore the importance of identification of SV events in OAC with implications for targeted therapies.

Published
2022
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8. Cellworks singula therapy response index (TRI) predicts clinical outcomes for esophageal adenocarcinoma: MyCare-004.

Author

Smyth, Elizabeth Catherine, primary, Watson, Drew, additional, Nutzinger, Barbara, additional, Castro, Michael P, additional, Kapoor, Shweta, additional, Prasad, Samiksha Avinash, additional, Rajagopalan, Swaminathan, additional, Cheah, Calvin, additional, Nair, Prashant Ramachandran, additional, Alam, Aftab, additional, Devonshire, Ginny, additional, Grehan, Nicola, additional, Suseela, Rakhi Purushothaman, additional, Tyagi, Anuj, additional, Agrawal, Ashish Kumar, additional, Azam, Humera, additional, Sauban, Mohammed, additional, Pampana, Anusha, additional, Macpherson, Michele Dundas, additional, and Fitzgerald, Rebecca C., additional

Published
2022
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10. Whole-genome sequencing of patients with rare diseases in a national health system

Author

Turro, Ernest, Astle, William J., Megy, Karyn, Gräf, Stefan, Greene, Daniel, Shamardina, Olga, Allen, Hana Lango, Sanchis-Juan, Alba, Frontini, Mattia, Thys, Chantal, Stephens, Jonathan, Mapeta, Rutendo, Burren, Oliver S., Downes, Kate, Haimel, Matthias, Tuna, Salih, Deevi, Sri V.V., Aitman, Timothy J., Bennett, David L., Calleja, Paul, Carss, Keren, Caulfield, Mark J., Chinnery, Patrick F., Dixon, Peter H., Gale, Daniel P., James, Roger, Koziell, Ania, Laffan, Michael A., Levine, Adam P., Maher, Eamonn R., Markus, Hugh S., Morales, Joannella, Morrell, Nicholas W., Mumford, Andrew D., Ormondroyd, Elizabeth, Rankin, Stuart, Rendon, Augusto, Richardson, Sylvia, Roberts, Irene, Roy, Noemi B.A., Saleem, Moin A., Smith, Kenneth G.C., Stark, Hannah, Tan, Rhea Y.Y., Themistocleous, Andreas C., Thrasher, Adrian J., Watkins, Hugh, Webster, Andrew R., Wilkins, Martin R., Williamson, Catherine, Whitworth, James, Humphray, Sean, Bentley, David R., Abbs, Stephen, Abulhoul, Lara, Adlard, Julian, Ahmed, Munaza, Alachkar, Hana, Allsup, David J., Almeida-King, Jeff, Ancliff, Philip, Antrobus, Richard, Armstrong, Ruth, Arno, Gavin, Ashford, Sofie, Attwood, Anthony, Aurora, Paul, Babbs, Christian, Bacchelli, Chiara, Bakchoul, Tamam, Banka, Siddharth, Bariana, Tadbir, Barwell, Julian, Batista, Joana, Baxendale, Helen E., Beales, Phil L., Bierzynska, Agnieszka, Biss, Tina, Bitner-Glindzicz, Maria A.K., Black, Graeme C., Bleda, Marta, Blesneac, Iulia, Bockenhauer, Detlef, Bogaard, Harm, Bourne, Christian J., Boyce, Sara, Bradley, John R., Bragin, Eugene, Breen, Gerome, Brennan, Paul, Brewer, Carole, Brown, Matthew, Browning, Andrew C., Browning, Michael J., Buchan, Rachel J., Buckland, Matthew S., Bueser, Teofila, Diz, Carmen Bugarin, Burn, John, Burns, Siobhan O., Burrows, Nigel, Campbell, Carolyn, Carr-White, Gerald, Casey, Ruth, Chambers, Jenny, Chambers, John, Chan, Melanie M.Y., Cheah, Calvin, Cheng, Floria, Chitre, Manali, Christian, Martin T., Church, Colin, Clayton-Smith, Jill, Cleary, Maureen, Brod, Naomi Clements, Coghlan, Gerry, Colby, Elizabeth, Cole, Trevor R.P., Collins, Janine, Collins, Peter W., Colombo, Camilla, Compton, Cecilia J., Condliffe, Robin, Cook, Stuart, Cook, H. Terence, Cooper, Nichola, Corris, Paul A A., Furnell, Abigail, Cunningham, Fiona, Curry, Nicola S., Cutler, Antony J., Daniels, Matthew J., Dattani, Mehul, Daugherty, Louise C., Davis, John, De Soyza, Anthony, Dent, Timothy, Deshpande, Charu, Dewhurst, Eleanor F., Douzgou, Sofia, Drazyk, Anna M., Drewe, Elizabeth, Duarte, Daniel, Dutt, Tina, Edgar, J. David M., Edwards, Karen, Egner, William, Ekani, Melanie N., Elliott, Perry, Erber, Wendy N., Erwood, Marie, Estiu, Maria C., Evans, Dafydd Gareth, Evans, Gillian, Everington, Tamara, Eyries, Mélanie, Fassihi, Hiva, Favier, Remi, Findhammer, Jack, Fletcher, Debra, Flinter, Frances A., Floto, R. Andres, Fowler, Tom, Fox, James, Frary, Amy J., French, Courtney E., Freson, Kathleen, Gall, Henning, Ganesan, Vijeya, Gattens, Michael, Geoghegan, Claire, Gerighty, Terence S.A., Gharavi, Ali G., Ghio, Stefano, Ghofrani, Hossein Ardeschir, Gibbs, J. Simon R., Gibson, Kate, Gilmour, Kimberly C., Girerd, Barbara, Gleadall, Nicholas S., Goddard, Sarah, Goldstein, David B., Gomez, Keith, Gordins, Pavels, Gosal, David, Graham, Jodie, Grassi, Luigi, Greenhalgh, Lynn, Greinacher, Andreas, Gresele, Paolo, Griffiths, Philip, Grigoriadou, Sofia, Grocock, Russell J., Grozeva, Detelina, Gurnell, Mark, Hackett, Scott, Hadinnapola, Charaka, Hague, William M., Hague, Rosie, Hall, Matthew, Hanson, Helen L., Haque, Eshika, Harkness, Kirsty, Harper, Andrew R., Harris, Claire L L., Hart, Daniel, Hassan, Ahamad, Hayman, Grant, Henderson, Alex, Herwadkar, Archana, Hoffman, Jonathan, Holden, Simon, Horvath, Rita, Houlden, Henry, Houweling, Arjan C C., Howard, Luke S., Hu, Fengyuan, Hudson, Gavin, Hughes, Joseph, Huissoon, Aarnoud P., Humbert, Marc, Hunter, Sarah, Hurles, Matthew, Irving, Melita, Izatt, Louise, Johnson, Sally A., Jolles, Stephen, Jolley, Jennifer, Josifova, Dragana, Jurkute, Neringa, Karten, Tim, Karten, Johannes, Kasanicki, Mary A., Kazkaz, Hanadi, Kazmi, Rashid, Kelleher, Peter, Kelly, Anne M., Kelsall, Wilf, Kempster, Carly, Kiely, David G., Kingston, Nathalie, Klima, Robert, Koelling, Nils, Kostadima, Myrto, Kovacs, Gabor, Kreuzhuber, Roman, Kuijpers, Taco W., Kumar, Ajith, Kumararatne, Dinakantha, Kurian, Manju A., Lalloo, Fiona, Lambert, Michele, Lawrie, Allan, Layton, D. Mark, Lench, Nick, Lentaigne, Claire, Lester, Tracy, Linger, Rachel, Longhurst, Hilary, Lorenzo, Lorena E., Louka, Eleni, Lyons, Paul A., Machado, Rajiv D., MacKenzie Ross, Robert V., Madan, Bella, Maimaris, Jesmeen, Malka, Samantha, Mangles, Sarah, Marchbank, Kevin J., Marks, Stephen, Marschall, Hanns Ulrich, Marshall, Andrew, Martin, Jennifer, Mathias, Mary, Matthews, Emma, Maxwell, Heather, McAlinden, Paul, McCarthy, Mark I., McKinney, Harriet, McMahon, Aoife, Meacham, Stuart, Mead, Adam J., Castello, Ignacio Medina, Mehta, Sarju G G., Michaelides, Michel, Millar, Carolyn, Mohammed, Shehla N., Moledina, Shahin, Montani, David, Moore, Anthony T., Mozere, Monika, Muir, Keith W., Nemeth, Andrea H., Newman, William G., Newnham, Michael, Noorani, Sadia, Nurden, Paquita, O’Sullivan, Jennifer, Obaji, Samya, Odhams, Chris, Okoli, Steven, Olschewski, Andrea, Olschewski, Horst, Ong, Kai Ren, Oram, S. Helen, Ouwehand, Willem H., Palles, Claire, Papadia, Sofia, Park, Soo Mi, Parry, David, Patel, Smita, Paterson, Joan, Peacock, Andrew, Pearce, Simon H H., Peden, John, Peerlinck, Kathelijne, Penkett, Christopher J., Pepke-Zaba, Joanna, Petersen, Romina, Pilkington, Clarissa, Poole, Kenneth E.S., Prathalingam, Radhika, Psaila, Bethan, Pyle, Angela, Quinton, Richard, Rahman, Shamima, Rao, Anupama, Raymond, F. Lucy, Rayner-Matthews, Paula J., Rees, Christine, Renton, Tara, Rhodes, Christopher J., Rice, Andrew S.C., Richter, Alex, Robert, Leema, Rogers, Anthony, Rose, Sarah J., Ross-Russell, Robert, Roughley, Catherine, Roy, Noemi B. A, Ruddy, Deborah M., Sadeghi-Alavijeh, Omid, Samani, Nilesh, Samarghitean, Crina, Sargur, Ravishankar B., Sarkany, Robert N., Satchell, Simon, Savic, Sinisa, Sayer, John A., Sayer, Genevieve, Scelsi, Laura, Schaefer, Andrew M., Schulman, Sol, Scott, Richard, Scully, Marie, Searle, Claire, Seeger, Werner, Sen, Arjune, Sewell, W. A.Carrock, Seyres, Denis, Shah, Neil, Shapiro, Susan E., Shaw, Adam C., Short, Patrick J., Sibson, Keith, Side, Lucy, Simeoni, Ilenia, Simpson, Michael A A., Sims, Matthew C., Sivapalaratnam, Suthesh, Smedley, Damian, Smith, Katherine R., Snape, Katie, Soranzo, Nicole, Soubrier, Florent, Southgate, Laura, Spasic-Boskovic, Olivera, Staines, Simon, Staples, Emily, Steward, Charles, Stirrups, Kathleen E., Stuckey, Alex, Suntharalingam, Jay, Swietlik, Emilia M., Syrris, Petros, Tait, R. Campbell, Talks, Kate, Tate, Katie, Taylor, John M., Taylor, Jenny C., Thaventhiran, James E., Thomas, Ellen, Thomas, David, Thomas, Moira J., Thomas, Patrick, Thomson, Kate, Threadgold, Glen, Tilly, Tobias, Tischkowitz, Marc, Titterton, Catherine, Todd, John A., Toh, Cheng Hock, Tolhuis, Bas, Tomlinson, Ian P., Toshner, Mark, Traylor, Matthew, Treacy, Carmen, Treadaway, Paul, Trembath, Richard, Turek, Wojciech, Twiss, Philip, Vale, Tom, Geet, Chris Van, Zuydam, Natalie van, Vandekuilen, Maarten, Vandersteen, Anthony M., Vazquez-Lopez, Marta, von Ziegenweidt, Julie, Vonk Noordegraaf, Anton, Wagner, Annette, Waisfisz, Quinten, Walker, Suellen M., Walker, Neil, Walter, Klaudia, Ware, James S., Watt, Christopher, Wedderburn, Lucy, Wei, Wei, Welch, Steven B., Wessels, Julie, Westbury, Sarah K., Westwood, John Paul, Wharton, John, Whitehorn, Deborah, Wilkie, Andrew O. M, Wilson, Brian T., Wong, Edwin K.S., Wood, Nicholas, Wood, Yvette, Woods, Christopher Geoffrey, Woodward, Emma R R., Wort, Stephen J., Worth, Austen, Wright, Michael, Yates, Katherine, Yong, Patrick F.K., Young, Timothy, Yu, Ping, Yu-Wai-Man, Patrick, Zlamalova, Eliska, University of Cambridge [UK] (CAM), John Wyeth & Brother Limited, Medical Research Council (MRC), Wellcome Trust, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Human genetics, ACS - Atherosclerosis & ischemic syndromes, Landsteiner Laboratory, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, and Project, NIHR BioResource for the 100,000 Genomes

Subjects
0301 basic medicine, Erythrocytes, Internationality, Databases, Factual, National Health Programs, [SDV]Life Sciences [q-bio], Disease, VARIANTS, Genome, State Medicine, NIHR BioResource for the 100,000 Genomes Project, 0302 clinical medicine, Medicine, GATA1 Transcription Factor, Genetics, Multidisciplinary, Translational bioinformatics, ASSOCIATION, 3. Good health, Multidisciplinary Sciences, Phenotype, 030220 oncology & carcinogenesis, disease genetics, Medical genetics, Science & Technology - Other Topics, Receptors, Thrombopoietin, medicine.medical_specialty, General Science & Technology, Quantitative Trait Loci, Genomics, Computational biology, Biology, DIAGNOSIS, computational biology and bioinformatics, Actin-Related Protein 2-3 Complex, Article, LRBA, LINKS, 03 medical and health sciences, Rare Diseases, Humans, Alleles, Adaptor Proteins, Signal Transducing, Whole genome sequencing, National health, Science & Technology, Whole Genome Sequencing, MUTATIONS, business.industry, THROMBOCYTOPENIA, United Kingdom, MACROTHROMBOCYTOPENIA, genetics research, 030104 developmental biology, business, Rare disease
Abstract

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

Published
2021

11. Serial circulating tumor DNA detection using a personalized, tumor-informed assay in esophageal adenocarcinoma patients following resection

Author

Ococks, Emma, Sharma, Shruti, Ng, Alvin Wei Tian, Consortium, OCCAMS, Aleshin, Alexey, Fitzgerald, Rebecca C, Smyth, Elizabeth, Edwards, Paul AW, Grehan, Nicola, Nutzinger, Barbara, Fidziukiewicz, Elwira, Redmond, Aisling M, Northrop, Alex, Abbas, Sujath, Smyth, Elizabeth C, O���Donovan, Maria, Miremadi, Ahmad, Malhotra, Shalini, Tripathi, Monika, Grantham, Amber, Cheah, Calvin, Coles, Hannah, Flint, Connor, Eldridge, Matthew, Secrier, Maria, Devonshire, Ginny, Jammula, Sriganesh, Davies, Jim, Crichton, Charles, Carroll, Nick, Hardwick, Richard H, Safranek, Peter, Hindmarsh, Andrew, Sujendran, Vijayendran, Hayes, Stephen J, Ang, Yeng, Sharrocks, Andrew, Preston, Shaun R, Bagwan, Izhar, Save, Vicki, Skipworth, Richard JE, Hupp, Ted R, O���Neill, J Robert, Tucker, Olga, Beggs, Andrew, Taniere, Philippe, Puig, Sonia, Contino, Gianmarco, Underwood, Timothy J, Walker, Robert C, Grace, Ben L, Lagergren, Jesper, Gossage, James, Mahadeva, Ula, Davies, Andrew, Chang, Fuju, Goh, Vicky, Ciccarelli, Francesca D, Sanders, Grant, Berrisford, Richard, Chan, David, Cheong, Ed, Kumar, Bhaskar, Sreedharan, L, Parsons, Simon L, Soomro, Irshad, Kaye, Philip, Saunders, John, Lovat, Laurence, Haidry, Rehan, Scott, Michael, Sothi, Sharmila, Lishman, Suzy, Hanna, George B, Moorthy, Krishna, Peters, Christopher J, Grabowska, Anna, Turkington, Richard, McManus, Damian, Coleman, Helen, and Petty, Russell D

Subjects
Genome Integrity & Repair, Gene Expression, Genetics & Genomics, Computational & Systems Biology
Abstract

No description supplied

Published
2021
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12. Cytosponge-trefoil factor 3 versus usual care to identify Barrett's oesophagus in a primary care setting: a multicentre, pragmatic, randomised controlled trial

Author

Fitzgerald, Rebecca C, primary, di Pietro, Massimiliano, additional, O'Donovan, Maria, additional, Maroni, Roberta, additional, Muldrew, Beth, additional, Debiram-Beecham, Irene, additional, Gehrung, Marcel, additional, Offman, Judith, additional, Tripathi, Monika, additional, Smith, Samuel G, additional, Aigret, Benoit, additional, Walter, Fiona M, additional, Rubin, Greg, additional, Sasieni, Peter, additional, Bagewadi, Abhay, additional, Patrick, Abigail, additional, Shenoy, Achuth, additional, Redmond, Aisling, additional, Muddu, Ajay, additional, Northrop, Alex, additional, Groves, Alice, additional, Shiner, Alice, additional, Heer, Amardeep, additional, Takhar, Amrit, additional, Bowles, Amy, additional, Jarman, Andrea, additional, Wong, Angela, additional, Lucas, Angie, additional, Gibbons, Anita, additional, Dhar, Anjan, additional, Curry, Anji, additional, Lalonde, Anna, additional, Swinburn, Anna, additional, Turner, Anne, additional, Lydon, Anne-Marie, additional, Gunstone, Anthony, additional, Lee, Arlene, additional, Nambi, Arul, additional, Ariyarathenam, Arun, additional, Elden, Ashley, additional, Wilson, Ashley, additional, Donepudi, Balaji, additional, Campbell, Barbara, additional, Uszycka, Basia, additional, Bowers, Ben, additional, Coghill, Ben, additional, de Quadros, Bruno, additional, Cheah, Calvin, additional, Bratten, Carla, additional, Brown, Carly, additional, Moorbey, Chantelle, additional, Clisby, Charles, additional, Gordon, Charles, additional, Schramm, Chris, additional, Castle, Chris, additional, Newark, Chris, additional, Norris, Chrissie, additional, A'Court, Christine, additional, Graham, Claire, additional, Fletcher, Clare, additional, Grocott, Clare, additional, Rees, Colin, additional, Bakker, Corinne, additional, Paschalides, Costas, additional, Vickery, Craig, additional, Schembri, Damian, additional, Morris, Danielle, additional, Hagan, Daryl, additional, Cronk, David, additional, Goddard, David, additional, Graham, David, additional, Phillips, Dean, additional, Prabhu, Deeksha, additional, Kejariwal, Deepak, additional, Garg, Dhirendra, additional, Lonsdale, Diane, additional, Butterworth, Dianne, additional, Clements, Donna, additional, Bradman, Drew, additional, Blake, Duncan, additional, Mather, Elizabeth, additional, O'Farrell, Ewan, additional, Markowetz, Florian, additional, Adams, Fran, additional, Pesola, Francesca, additional, Forbes, Gareth, additional, Taylor, Gary, additional, Collins, Glenn, additional, Irvine, Gordon, additional, Fourie, Gysbert, additional, Doyle, Harriet, additional, Barnes, Heather, additional, Bowyer, Helen, additional, Whiting, Helen, additional, Beales, Ian, additional, Binnian, Ian, additional, Bremner, Ian, additional, Jennings, Ian, additional, Troiceanu, Ilona, additional, Modelell, Ines, additional, Emmerson, Ingrid, additional, Ortiz, Jacobo, additional, Lilley, Jacqueline, additional, Harvey, Jacquelyn, additional, Vicars, Jacqui, additional, Takhar, Jagjit, additional, Larcombe, James, additional, Bornschein, Jan, additional, Aldegather, Jehad, additional, Johnson, Jenny, additional, Ducker, Jill, additional, Skinner, Jo, additional, Dash, Joanne, additional, Walsh, Joanne, additional, Miralles, Jose, additional, Ridgway, Josephine, additional, Ince, Julia, additional, Kennedy, Julie, additional, Hampson, Kat, additional, Milne, Kate, additional, Ellerby, Katherine, additional, Priddis, Katherine, additional, Rainsbury, Kathy, additional, Powell, Kelly, additional, Gunner, Kerry, additional, Ragunath, Krish, additional, Knox, Kyle, additional, Baseley, Laura, additional, White, Lauren, additional, Lovat, Laurence, additional, Berney, Lee, additional, Crockett, Lindsay, additional, Murray, Lisa, additional, Westwood, Lisa, additional, Chalkley, Lisa, additional, Leggett, Loraine, additional, Dale, Louise, additional, Scovell, Louise, additional, Brooks, Lucy, additional, Saunders, Lucy, additional, Owen, Lydia, additional, Dilwershah, Maria, additional, Baldry, Marie, additional, Corcoran, Marie, additional, Roy, Marie, additional, Macedo, Mario, additional, Attah, Mark, additional, Anson, Mary-Jo, additional, Rutter, Matt, additional, Wallard, Matthew, additional, Gaw, Matthew, additional, Hunt, Matthew, additional, Lea-Hagerty, Megan, additional, Penacerrada, Melchizedek, additional, Bianchi, Michele, additional, Baker-Moffatt, Michelle, additional, Czajkowski, Michelle, additional, Sleeth, Michelle, additional, Brewer, Nick, additional, Wooding, Nick, additional, Todd, Nicky, additional, Millen, Nicola, additional, Zolle, Olga, additional, Whitehead, Orla, additional, Ojechi, Patrick, additional, Moore, Patrick, additional, Banim, Paul, additional, Spellar, Paula, additional, Bhandari, Pradeep, additional, Kant, Prashant, additional, Nixon, Rachel, additional, Russell, Rebecca, additional, Roberts, Rebekah, additional, Skule, Rene, additional, West, Richard, additional, Fox, Robin, additional, Beesley, Ruth, additional, Gibbins, Ruth, additional, Osborne, Ruth, additional, Thiagarajan, S, additional, Bastiman, Sally, additional, Warburton, Samantha, additional, Pai, Samir, additional, Leith-Russell, Sarah, additional, Utting, Sarah, additional, Watson, Sarah, additional, Wytrykowski, Sarah, additional, Singh, Satish, additional, Malhotra, Shalini, additional, Woods, Sharon, additional, Conway, Shaun, additional, Mateer, Sherrie, additional, Macrae, Shona, additional, Singh, Shruti, additional, Fourie, Simona, additional, Campbell, Siobhan, additional, Parslow-Williams, Siobhan, additional, Goel, Sonica, additional, Dellar, Stephen, additional, Jones, Stephen, additional, Knight, Steve, additional, Mackay-Thomas, Stuart, additional, Mukherjee, Stuti, additional, Allen, Sue, additional, Henry, Suzanne, additional, Evans, Tara, additional, Leighton, Theresa, additional, Bray, Tim, additional, Shackleton, Tom, additional, Santosh, Vanaja, additional, Glover, Vicki, additional, Chandraraj, Vijay, additional, Elson, Will, additional, Briggs, William, additional, Barron, Zoe, additional, and Khan, Zohrah, additional

Published
2020
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13. Transcriptomic profiling reveals three molecular phenotypes of adenocarcinoma at the gastroesophageal junction

Author

Bornschein, Jan, Wernisch, Lorenz, Secrier, Maria, Miremadi, Ahmad, Perner, Juliane, MacRae, Shona, O'Donovan, Maria, Newton, Richard, Menon, Suraj, Bower, Lawrence, Eldridge, Matthew D, Devonshire, Ginny, Cheah, Calvin, Turkington, Richard, Hardwick, Richard H, Selgrad, Michael, Venerito, Marino, Malfertheiner, Peter, OCCAMS Consortium, Fitzgerald, Rebecca C, Eldridge, Matthew [0000-0002-5799-8911], Fitzgerald, Rebecca [0000-0002-3434-3568], and Apollo - University of Cambridge Repository

Subjects
esophageal adenocarcinoma, gastric cancer, gene expression profiling, gastroesophageal junction, Siewert classification
Abstract

Cancers occurring at the gastroesophageal junction (GEJ) are classified as predominantly esophageal or gastric, which is often difficult to decipher. We hypothesized that the transcriptomic profile might reveal molecular subgroups which could help to define the tumor origin and behavior beyond anatomical location. The gene expression profiles of 107 treatment-naïve, intestinal type, gastroesophageal adenocarcinomas were assessed by the Illumina-HTv4.0 beadchip. Differential gene expression (limma), unsupervised subgroup assignment (mclust) and pathway analysis (gage) were undertaken in R statistical computing and results were related to demographic and clinical parameters. Unsupervised assignment of the gene expression profiles revealed three distinct molecular subgroups, which were not associated with anatomical location, tumor stage or grade (p > 0.05). Group 1 was enriched for pathways involved in cell turnover, Group 2 was enriched for metabolic processes and Group 3 for immune-response pathways. Patients in group 1 showed the worst overall survival (p = 0.019). Key genes for the three subtypes were confirmed by immunohistochemistry. The newly defined intrinsic subtypes were analyzed in four independent datasets of gastric and esophageal adenocarcinomas with transcriptomic data available (RNAseq data: OCCAMS cohort, n = 158; gene expression arrays: Belfast, n = 63; Singapore, n = 191; Asian Cancer Research Group, n = 300). The subgroups were represented in the independent cohorts and pooled analysis confirmed the prognostic effect of the new subtypes. In conclusion, adenocarcinomas at the GEJ comprise three distinct molecular phenotypes which do not reflect anatomical location but rather inform our understanding of the key pathways expressed.

Published
2019
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14. Multi-Omic Analysis of Esophageal Adenocarcinoma Uncovers Candidate Therapeutic Targets and Cancer-Selective Posttranscriptional Regulation

Author

O'Neill, J. Robert, Yébenes Mayordomo, Marcos, Mitulović, Goran, Al Shboul, Sofian, Bedran, Georges, Faktor, Jakub, Hernychova, Lenka, Uhrik, Lukas, Gómez-Herranz, Maria, Kocikowski, Mikołaj, Save, Vicki, Vojtěšek, Bořivoj, Arends, Mark J., Fitzgerald, Rebecca C., Edwards, Paul A.W., Grehan, Nicola, Nutzinger, Barbara, Loreno, Christine, Redmond, Aisling M., Abbas, Sujath, Freeman, Adam, Smyth, Elizabeth C., O'Donovan, Maria, Miremadi, Ahmad, Malhotra, Shalini, Tripathi, Monika, Cheah, Calvin, Coles, Hannah, Millington, Curtis, Devonshire, Ginny, Eldridge, Matthew, Secrier, Maria, Jammula, Sriganesh, Davies, Jim, Crichton, Charles, Carroll, Nick, Hardwick, Richard H., Safranek, Peter, Hindmarsh, Andrew, Sujendran, Vijayendran, Hayes, Stephen J., Ang, Yeng, Sharrocks, Andrew, Preston, Shaun R., Bagwan, Izhar, Save, Vicki, Skipworth, Richard J.E., Hupp, Ted R., O'Neill, J Robert, Tucker, Olga, Beggs, Andrew, Taniere, Philippe, Puig, Sonia, Contino, Gianmarco, Underwood, Timothy J., Walker, Robert C., Grace, Ben L., Lagergren, Jesper, Gossage, James, Davies, Andrew, Chang, Fuju, Mahadeva, Ula, Goh, Vicky, Ciccarelli, Francesca D., Sanders, Grant, Berrisford, Richard, Chan, David, Cheong, Ed, Kumar, Bhaskar, Sreedharan, L., Parsons, Simon L., Soomro, Irshad, Kaye, Philip, Saunders, John, Lovat, Laurence, Haidry, Rehan, Scott, Michael, Sothi, Sharmila, Lishman, Suzy, Hanna, George B., Peters, Christopher J., Moorthy, Krishna, Grabowska, Anna, Turkington, Richard, McManus, Damian, Coleman, Helen, Petty, Russell D., Bartlet, Freddie, Hupp, Ted, and Alfaro, Javier Antonio

Abstract

Efforts to address the poor prognosis associated with esophageal adenocarcinoma (EAC) have been hampered by a lack of biomarkers to identify early disease and therapeutic targets. Despite extensive efforts to understand the somatic mutations associated with EAC over the past decade, a gap remains in understanding how the atlas of genomic aberrations in this cancer impacts the proteome and which somatic variants are of importance for the disease phenotype. We performed a quantitative proteomic analysis of 23 EACs and matched adjacent normal esophageal and gastric tissues. We explored the correlation of transcript and protein abundance using tissue-matched RNA-seq and proteomic data from seven patients and further integrated these data with a cohort of EAC RNA-seq data (n = 264 patients), EAC whole-genome sequencing (n = 454 patients), and external published datasets. We quantified protein expression from 5879 genes in EAC and patient-matched normal tissues. Several biomarker candidates with EAC-selective expression were identified, including the transmembrane protein GPA33. We further verified the EAC-enriched expression of GPA33 in an external cohort of 115 patients and confirm this as an attractive diagnostic and therapeutic target. To further extend the insights gained from our proteomic data, an integrated analysis of protein and RNA expression in EAC and normal tissues revealed several genes with poorly correlated protein and RNA abundance, suggesting posttranscriptional regulation of protein expression. These outlier genes, including SLC25A30, TAOK2, and AGMAT, only rarely demonstrated somatic mutation, suggesting post-transcriptional drivers for this EAC-specific phenotype. AGMAT was demonstrated to be overexpressed at the protein level in EAC compared to adjacent normal tissues with an EAC-selective, post-transcriptional mechanism of regulation of protein abundance proposed. Integrated analysis of proteome, transcriptome, and genome in EAC has revealed several genes with tumor-selective, posttranscriptional regulation of protein expression, which may be an exploitable vulnerability.

Published
2024
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19. Transcriptomic profiling reveals three molecular phenotypes of adenocarcinoma at the gastroesophageal junction.

Author

Bornschein J, Wernisch L, Secrier M, Miremadi A, Perner J, MacRae S, O'Donovan M, Newton R, Menon S, Bower L, Eldridge MD, Devonshire G, Cheah C, Turkington R, Hardwick RH, Selgrad M, Venerito M, Malfertheiner P, and Fitzgerald RC

Subjects
Gene Expression Profiling methods, Humans, Immunohistochemistry methods, Phenotype, Prognosis, Prospective Studies, Adenocarcinoma genetics, Adenocarcinoma pathology, Esophageal Neoplasms genetics, Esophageal Neoplasms pathology, Esophagogastric Junction pathology, Stomach Neoplasms genetics, Stomach Neoplasms pathology, Transcriptome genetics
Abstract

Cancers occurring at the gastroesophageal junction (GEJ) are classified as predominantly esophageal or gastric, which is often difficult to decipher. We hypothesized that the transcriptomic profile might reveal molecular subgroups which could help to define the tumor origin and behavior beyond anatomical location. The gene expression profiles of 107 treatment-naïve, intestinal type, gastroesophageal adenocarcinomas were assessed by the Illumina-HTv4.0 beadchip. Differential gene expression (limma), unsupervised subgroup assignment (mclust) and pathway analysis (gage) were undertaken in R statistical computing and results were related to demographic and clinical parameters. Unsupervised assignment of the gene expression profiles revealed three distinct molecular subgroups, which were not associated with anatomical location, tumor stage or grade (p > 0.05). Group 1 was enriched for pathways involved in cell turnover, Group 2 was enriched for metabolic processes and Group 3 for immune-response pathways. Patients in group 1 showed the worst overall survival (p = 0.019). Key genes for the three subtypes were confirmed by immunohistochemistry. The newly defined intrinsic subtypes were analyzed in four independent datasets of gastric and esophageal adenocarcinomas with transcriptomic data available (RNAseq data: OCCAMS cohort, n = 158; gene expression arrays: Belfast, n = 63; Singapore, n = 191; Asian Cancer Research Group, n = 300). The subgroups were represented in the independent cohorts and pooled analysis confirmed the prognostic effect of the new subtypes. In conclusion, adenocarcinomas at the GEJ comprise three distinct molecular phenotypes which do not reflect anatomical location but rather inform our understanding of the key pathways expressed., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Published
2019
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