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1. Metareview-informed Explainable Cytokine Storm Detection during CAR-T cell Therapy

Author

Bogatu, Alex, Wysocka, Magdalena, Wysocki, Oskar, Butterworth, Holly, Landers, Donal, Kilgour, Elaine, and Freitas, Andre

Subjects
Quantitative Biology - Quantitative Methods, Computer Science - Machine Learning
Abstract

Cytokine release syndrome (CRS), also known as cytokine storm, is one of the most consequential adverse effects of chimeric antigen receptor therapies that have shown promising results in cancer treatment. When emerging, CRS could be identified by the analysis of specific cytokine and chemokine profiles that tend to exhibit similarities across patients. In this paper, we exploit these similarities using machine learning algorithms and set out to pioneer a meta--review informed method for the identification of CRS based on specific cytokine peak concentrations and evidence from previous clinical studies. We argue that such methods could support clinicians in analyzing suspect cytokine profiles by matching them against CRS knowledge from past clinical studies, with the ultimate aim of swift CRS diagnosis. During evaluation with real--world CRS clinical data, we emphasize the potential of our proposed method of producing interpretable results, in addition to being effective in identifying the onset of cytokine storm.

Published
2022

5. supplementary Table 5 from Identification of Pharmacodynamic Transcript Biomarkers in Response to FGFR Inhibition by AZD4547

Author

Delpuech, Oona, primary, Rooney, Claire, primary, Mooney, Lorraine, primary, Baker, Dawn, primary, Shaw, Robert, primary, Dymond, Michael, primary, Wang, Dennis, primary, Zhang, Pei, primary, Cross, Sarah, primary, Veldman-Jones, Margaret, primary, Wilson, Joanne, primary, Davies, Barry R., primary, Dry, Jonathan R., primary, Kilgour, Elaine, primary, and Smith, Paul D., primary

Published
2023
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6. Data from High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial

Author

Pearson, Alex, primary, Smyth, Elizabeth, primary, Babina, Irina S., primary, Herrera-Abreu, Maria Teresa, primary, Tarazona, Noelia, primary, Peckitt, Clare, primary, Kilgour, Elaine, primary, Smith, Neil R., primary, Geh, Catherine, primary, Rooney, Claire, primary, Cutts, Ros, primary, Campbell, James, primary, Ning, Jian, primary, Fenwick, Kerry, primary, Swain, Amanda, primary, Brown, Gina, primary, Chua, Sue, primary, Thomas, Anne, primary, Johnston, Stephen R.D., primary, Ajaz, Mazhar, primary, Sumpter, Katherine, primary, Gillbanks, Angela, primary, Watkins, David, primary, Chau, Ian, primary, Popat, Sanjay, primary, Cunningham, David, primary, and Turner, Nicholas C., primary

Published
2023
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7. supplementary Table1 from Identification of Pharmacodynamic Transcript Biomarkers in Response to FGFR Inhibition by AZD4547

Author

Delpuech, Oona, primary, Rooney, Claire, primary, Mooney, Lorraine, primary, Baker, Dawn, primary, Shaw, Robert, primary, Dymond, Michael, primary, Wang, Dennis, primary, Zhang, Pei, primary, Cross, Sarah, primary, Veldman-Jones, Margaret, primary, Wilson, Joanne, primary, Davies, Barry R., primary, Dry, Jonathan R., primary, Kilgour, Elaine, primary, and Smith, Paul D., primary

Published
2023
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8. Supplementary Figure 1 from High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial

Author

Pearson, Alex, primary, Smyth, Elizabeth, primary, Babina, Irina S., primary, Herrera-Abreu, Maria Teresa, primary, Tarazona, Noelia, primary, Peckitt, Clare, primary, Kilgour, Elaine, primary, Smith, Neil R., primary, Geh, Catherine, primary, Rooney, Claire, primary, Cutts, Ros, primary, Campbell, James, primary, Ning, Jian, primary, Fenwick, Kerry, primary, Swain, Amanda, primary, Brown, Gina, primary, Chua, Sue, primary, Thomas, Anne, primary, Johnston, Stephen R.D., primary, Ajaz, Mazhar, primary, Sumpter, Katherine, primary, Gillbanks, Angela, primary, Watkins, David, primary, Chau, Ian, primary, Popat, Sanjay, primary, Cunningham, David, primary, and Turner, Nicholas C., primary

Published
2023
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9. Data from Identification of Pharmacodynamic Transcript Biomarkers in Response to FGFR Inhibition by AZD4547

Author

Delpuech, Oona, primary, Rooney, Claire, primary, Mooney, Lorraine, primary, Baker, Dawn, primary, Shaw, Robert, primary, Dymond, Michael, primary, Wang, Dennis, primary, Zhang, Pei, primary, Cross, Sarah, primary, Veldman-Jones, Margaret, primary, Wilson, Joanne, primary, Davies, Barry R., primary, Dry, Jonathan R., primary, Kilgour, Elaine, primary, and Smith, Paul D., primary

Published
2023
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10. Supplementary Figure 6 from High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial

Author

Pearson, Alex, primary, Smyth, Elizabeth, primary, Babina, Irina S., primary, Herrera-Abreu, Maria Teresa, primary, Tarazona, Noelia, primary, Peckitt, Clare, primary, Kilgour, Elaine, primary, Smith, Neil R., primary, Geh, Catherine, primary, Rooney, Claire, primary, Cutts, Ros, primary, Campbell, James, primary, Ning, Jian, primary, Fenwick, Kerry, primary, Swain, Amanda, primary, Brown, Gina, primary, Chua, Sue, primary, Thomas, Anne, primary, Johnston, Stephen R.D., primary, Ajaz, Mazhar, primary, Sumpter, Katherine, primary, Gillbanks, Angela, primary, Watkins, David, primary, Chau, Ian, primary, Popat, Sanjay, primary, Cunningham, David, primary, and Turner, Nicholas C., primary

Published
2023
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11. supplementary Table 6 from Identification of Pharmacodynamic Transcript Biomarkers in Response to FGFR Inhibition by AZD4547

Author

Delpuech, Oona, primary, Rooney, Claire, primary, Mooney, Lorraine, primary, Baker, Dawn, primary, Shaw, Robert, primary, Dymond, Michael, primary, Wang, Dennis, primary, Zhang, Pei, primary, Cross, Sarah, primary, Veldman-Jones, Margaret, primary, Wilson, Joanne, primary, Davies, Barry R., primary, Dry, Jonathan R., primary, Kilgour, Elaine, primary, and Smith, Paul D., primary

Published
2023
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12. supplementary figure and table legend from Identification of Pharmacodynamic Transcript Biomarkers in Response to FGFR Inhibition by AZD4547

Author

Delpuech, Oona, primary, Rooney, Claire, primary, Mooney, Lorraine, primary, Baker, Dawn, primary, Shaw, Robert, primary, Dymond, Michael, primary, Wang, Dennis, primary, Zhang, Pei, primary, Cross, Sarah, primary, Veldman-Jones, Margaret, primary, Wilson, Joanne, primary, Davies, Barry R., primary, Dry, Jonathan R., primary, Kilgour, Elaine, primary, and Smith, Paul D., primary

Published
2023
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13. supplementary Table 3 from Identification of Pharmacodynamic Transcript Biomarkers in Response to FGFR Inhibition by AZD4547

Author

Delpuech, Oona, primary, Rooney, Claire, primary, Mooney, Lorraine, primary, Baker, Dawn, primary, Shaw, Robert, primary, Dymond, Michael, primary, Wang, Dennis, primary, Zhang, Pei, primary, Cross, Sarah, primary, Veldman-Jones, Margaret, primary, Wilson, Joanne, primary, Davies, Barry R., primary, Dry, Jonathan R., primary, Kilgour, Elaine, primary, and Smith, Paul D., primary

Published
2023
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14. Supplementary Figure Legends, Tables 1 - 3 from High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial

Author

Pearson, Alex, primary, Smyth, Elizabeth, primary, Babina, Irina S., primary, Herrera-Abreu, Maria Teresa, primary, Tarazona, Noelia, primary, Peckitt, Clare, primary, Kilgour, Elaine, primary, Smith, Neil R., primary, Geh, Catherine, primary, Rooney, Claire, primary, Cutts, Ros, primary, Campbell, James, primary, Ning, Jian, primary, Fenwick, Kerry, primary, Swain, Amanda, primary, Brown, Gina, primary, Chua, Sue, primary, Thomas, Anne, primary, Johnston, Stephen R.D., primary, Ajaz, Mazhar, primary, Sumpter, Katherine, primary, Gillbanks, Angela, primary, Watkins, David, primary, Chau, Ian, primary, Popat, Sanjay, primary, Cunningham, David, primary, and Turner, Nicholas C., primary

Published
2023
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15. Supplementary Figure 2 from High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial

Author

Pearson, Alex, primary, Smyth, Elizabeth, primary, Babina, Irina S., primary, Herrera-Abreu, Maria Teresa, primary, Tarazona, Noelia, primary, Peckitt, Clare, primary, Kilgour, Elaine, primary, Smith, Neil R., primary, Geh, Catherine, primary, Rooney, Claire, primary, Cutts, Ros, primary, Campbell, James, primary, Ning, Jian, primary, Fenwick, Kerry, primary, Swain, Amanda, primary, Brown, Gina, primary, Chua, Sue, primary, Thomas, Anne, primary, Johnston, Stephen R.D., primary, Ajaz, Mazhar, primary, Sumpter, Katherine, primary, Gillbanks, Angela, primary, Watkins, David, primary, Chau, Ian, primary, Popat, Sanjay, primary, Cunningham, David, primary, and Turner, Nicholas C., primary

Published
2023
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16. Supplementary figures from Identification of Pharmacodynamic Transcript Biomarkers in Response to FGFR Inhibition by AZD4547

Author

Delpuech, Oona, primary, Rooney, Claire, primary, Mooney, Lorraine, primary, Baker, Dawn, primary, Shaw, Robert, primary, Dymond, Michael, primary, Wang, Dennis, primary, Zhang, Pei, primary, Cross, Sarah, primary, Veldman-Jones, Margaret, primary, Wilson, Joanne, primary, Davies, Barry R., primary, Dry, Jonathan R., primary, Kilgour, Elaine, primary, and Smith, Paul D., primary

Published
2023
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17. Supplementary Figure 3 from High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial

Author

Pearson, Alex, primary, Smyth, Elizabeth, primary, Babina, Irina S., primary, Herrera-Abreu, Maria Teresa, primary, Tarazona, Noelia, primary, Peckitt, Clare, primary, Kilgour, Elaine, primary, Smith, Neil R., primary, Geh, Catherine, primary, Rooney, Claire, primary, Cutts, Ros, primary, Campbell, James, primary, Ning, Jian, primary, Fenwick, Kerry, primary, Swain, Amanda, primary, Brown, Gina, primary, Chua, Sue, primary, Thomas, Anne, primary, Johnston, Stephen R.D., primary, Ajaz, Mazhar, primary, Sumpter, Katherine, primary, Gillbanks, Angela, primary, Watkins, David, primary, Chau, Ian, primary, Popat, Sanjay, primary, Cunningham, David, primary, and Turner, Nicholas C., primary

Published
2023
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18. supplementary Table 2 from Identification of Pharmacodynamic Transcript Biomarkers in Response to FGFR Inhibition by AZD4547

Author

Delpuech, Oona, primary, Rooney, Claire, primary, Mooney, Lorraine, primary, Baker, Dawn, primary, Shaw, Robert, primary, Dymond, Michael, primary, Wang, Dennis, primary, Zhang, Pei, primary, Cross, Sarah, primary, Veldman-Jones, Margaret, primary, Wilson, Joanne, primary, Davies, Barry R., primary, Dry, Jonathan R., primary, Kilgour, Elaine, primary, and Smith, Paul D., primary

Published
2023
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19. Supplementary Figure 5 from High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial

Author

Pearson, Alex, primary, Smyth, Elizabeth, primary, Babina, Irina S., primary, Herrera-Abreu, Maria Teresa, primary, Tarazona, Noelia, primary, Peckitt, Clare, primary, Kilgour, Elaine, primary, Smith, Neil R., primary, Geh, Catherine, primary, Rooney, Claire, primary, Cutts, Ros, primary, Campbell, James, primary, Ning, Jian, primary, Fenwick, Kerry, primary, Swain, Amanda, primary, Brown, Gina, primary, Chua, Sue, primary, Thomas, Anne, primary, Johnston, Stephen R.D., primary, Ajaz, Mazhar, primary, Sumpter, Katherine, primary, Gillbanks, Angela, primary, Watkins, David, primary, Chau, Ian, primary, Popat, Sanjay, primary, Cunningham, David, primary, and Turner, Nicholas C., primary

Published
2023
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20. Supplementary Figure 4 from High-Level Clonal FGFR Amplification and Response to FGFR Inhibition in a Translational Clinical Trial

Author

Pearson, Alex, primary, Smyth, Elizabeth, primary, Babina, Irina S., primary, Herrera-Abreu, Maria Teresa, primary, Tarazona, Noelia, primary, Peckitt, Clare, primary, Kilgour, Elaine, primary, Smith, Neil R., primary, Geh, Catherine, primary, Rooney, Claire, primary, Cutts, Ros, primary, Campbell, James, primary, Ning, Jian, primary, Fenwick, Kerry, primary, Swain, Amanda, primary, Brown, Gina, primary, Chua, Sue, primary, Thomas, Anne, primary, Johnston, Stephen R.D., primary, Ajaz, Mazhar, primary, Sumpter, Katherine, primary, Gillbanks, Angela, primary, Watkins, David, primary, Chau, Ian, primary, Popat, Sanjay, primary, Cunningham, David, primary, and Turner, Nicholas C., primary

Published
2023
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21. supplementary Table 4 from Identification of Pharmacodynamic Transcript Biomarkers in Response to FGFR Inhibition by AZD4547

Author

Delpuech, Oona, primary, Rooney, Claire, primary, Mooney, Lorraine, primary, Baker, Dawn, primary, Shaw, Robert, primary, Dymond, Michael, primary, Wang, Dennis, primary, Zhang, Pei, primary, Cross, Sarah, primary, Veldman-Jones, Margaret, primary, Wilson, Joanne, primary, Davies, Barry R., primary, Dry, Jonathan R., primary, Kilgour, Elaine, primary, and Smith, Paul D., primary

Published
2023
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22. Body composition and lung cancer-associated cachexia in TRACERx

Author

Al-Sawaf, Othman, Weiss, Jakob, Skrzypski, Marcin, Lam, Jie Min, Karasaki, Takahiro, Zambrana, Francisco, Kidd, Andrew C, Frankell, Alexander M, Watkins, Thomas BK, Martinez-Ruiz, Carlos, Puttick, Clare, Black, James RM, Huebner, Ariana, Al Bakir, Maise, Sokac, Mateo, Collins, Susie, Veeriah, Selvaraju, Magno, Neil, Naceur-Lombardelli, Cristina, Prymas, Paulina, Toncheva, Antonia, Ward, Sophia, Jayanth, Nick, Salgado, Roberto, Bridge, Christopher P, Christiani, David C, Mak, Raymond H, Bay, Camden, Rosenthal, Michael, Sattar, Naveed, Welsh, Paul, Liu, Ying, Perrimon, Norbert, Popuri, Karteek, Beg, Mirza Faisal, McGranahan, Nicholas, Hackshaw, Allan, Breen, Danna M, O'Rahilly, Stephen, Birkbak, Nicolai J, Aerts, Hugo JWL, Jamal-Hanjani, Mariam, Swanton, Charles, Lester, Jason F, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Fennell, Dean A, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joan, Primrose, Lindsay, Boleti, Ekaterini, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Price, Gillian, Kerr, Keith M, Benafif, Sarah, Gilbert, Kayleigh, Naidu, Babu, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Middleton, Gary, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Lindsay, Colin R, Blackhall, Fiona H, Krebs, Matthew G, Summers, Yvonne, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Dive, Caroline, Schwarz, Roland F, Kaufmann, Tom L, Wilson, Gareth A, Rosenthal, Rachel, Van Loo, Peter, Szallasi, Zoltan, Kisistok, Judit, Diossy, Miklos, Demeulemeester, Jonas, Bunkum, Abigail, Stewart, Aengus, Magness, Alastair, Rowan, Andrew, Karamani, Angeliki, Chain, Benny, Campbell, Brittany B, Castignani, Carla, Bailey, Chris, Abbosh, Christopher, Weeden, Clare E, Lee, Claudia, Richard, Corentin, Hiley, Crispin T, Moore, David A, Pearce, David R, Karagianni, Despoina, Biswas, Dhruva, Levi, Dina, Hoxha, Elena, Cadieux, Elizabeth Larose, Lim, Emilia L, Colliver, Emma, Nye, Emma, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Gimeno-Valiente, Francisco, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Zhai, Haoran, Lowe, Helen L, Matos, Ignacio Garcia, Goldman, Jacki, Reading, James L, Herrero, Javier, Rane, Jayant K, Nicod, Jerome, Hartley, John A, Peggs, Karl S, Enfield, Katey SS, Selvaraju, Kayalvizhi, Thol, Kerstin, Litchfield, Kevin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Grigoriadis, Kristiana, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Duran, Marcos Vasquez, Litovchenko, Maria, Sunderland, Mariana Werner, Hill, Mark S, Dietzen, Michelle, Leung, Michelle, Escudero, Mickael, Angelova, Mihaela, Tanic, Miljana, Sivakumar, Monica, Kanu, Nnennaya, Chervova, Olga, Lucas, Olivia, Pich, Oriol, Hobson, Philip, Pawlik, Piotr, Stone, Richard Kevin, Bentham, Robert, Hynds, Robert E, Vendramin, Roberto, Saghafinia, Sadegh, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Quezada, Sergio A, Vanloo, Sharon, Zaccaria, Simone, Hessey, Sonya, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Marafioti, Teresa, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Liu, Wing Kin, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Forster, Martin D, Lee, Siow Ming, Borg, Elaine, Falzon, Mary, Papadatos-Pastos, Dionysis, Wilson, James, Ahmad, Tanya, Procter, Alexander James, Ahmed, Asia, Taylor, Magali N, Nair, Arjun, Lawrence, David, Patrini, Davide, Navani, Neal, Thakrar, Ricky M, Janes, Sam M, Hoogenboom, Emilie Martinoni, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Cave, Judith, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, Lim, Eric, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Nicholson, Andrew G, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Hewish, Madeleine, Danson, Sarah, Shackcloth, Michael J, Robinson, Lily, Russell, Peter, Blyth, Kevin G, Dick, Craig, Le Quesne, John, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
Male, Proteomics, Cachexia, Lung Neoplasms, Antigens, Neoplasm, Carcinoma, Non-Small-Cell Lung, Body Weight, Body Composition, Humans, Neoplasm Recurrence, Local, Muscle, Skeletal, Neoplasm Proteins
Abstract

Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC. ispartof: NATURE MEDICINE vol:29 issue:4 ispartof: location:United States status: Published online

Published
2023

23. The evolution of non-small cell lung cancer metastases in TRACERx

Author

Al Bakir, Maise, Huebner, Ariana, Martinez-Ruiz, Carlos, Grigoriadis, Kristiana, Watkins, Thomas BK, Pich, Oriol, Moore, David A, Veeriah, Selvaraju, Ward, Sophia, Laycock, Joanne, Johnson, Diana, Rowan, Andrew, Razaq, Maryam, Akther, Mita, Naceur-Lombardelli, Cristina, Prymas, Paulina, Toncheva, Antonia, Hessey, Sonya, Dietzen, Michelle, Colliver, Emma, Frankell, Alexander, Bunkum, Abigail, Lim, Emilia L, Karasaki, Takahiro, Abbosh, Christopher, Hiley, Crispin T, Hill, Mark S, Cook, Daniel E, Wilson, Gareth A, Salgado, Roberto, Nye, Emma, Stone, Richard Kevin, Fennell, Dean A, Price, Gillian, Kerr, Keith M, Naidu, Babu, Middleton, Gary, Summers, Yvonne, Lindsay, Colin R, Blackhall, Fiona H, Cave, Judith, Blyth, Kevin G, Nair, Arjun, Ahmed, Asia, Taylor, Magali N, Procter, Alexander James, Falzon, Mary, Lawrence, David, Navani, Neal, Thakrar, Ricky M, Janes, Sam M, Papadatos-Pastos, Dionysis, Forster, Martin D, Lee, Siow Ming, Ahmad, Tanya, Quezada, Sergio, Peggs, Karl S, Van Loo, Peter, Dive, Caroline, Hackshaw, Allan, Birkbak, Nicolai J, Zaccaria, Simone, Jamal-Hanjani, Mariam, McGranahan, Nicholas, Swanton, Charles, Lester, Jason F, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joan, Primrose, Lindsay, Boleti, Ekaterini, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Benafif, Sarah, Gilbert, Kayleigh, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Krebs, Matthew G, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Aerts, Hugo JWL, Schwarz, Roland F, Kaufmann, Tom L, Rosenthal, Rachel, Szallasi, Zoltan, Kisistok, Judit, Sokac, Mateo, Diossy, Miklos, Demeulemeester, Jonas, Stewart, Aengus, Magness, Alastair, Karamani, Angeliki, Chain, Benny, Campbell, Brittany B, Castignani, Carla, Bailey, Chris, Puttick, Clare, Weeden, Clare E, Lee, Claudia, Richard, Corentin, Pearce, David R, Karagianni, Despoina, Biswas, Dhruva, Levi, Dina, Hoxha, Elena, Larose Cadieux, Elizabeth, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Gimeno-Valiente, Francisco, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Zhai, Haoran, Lowe, Helen L, Matos, Ignacio, Goldman, Jacki, Reading, James L, Black, James RM, Herrero, Javier, Rane, Jayant K, Nicod, Jerome, Lam, Jie Min, Hartley, John A, Enfield, Katey SS, Selvaraju, Kayalvizhi, Thol, Kerstin, Litchfield, Kevin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Vasquez, Marcos, Litovchenko, Maria, Werner Sunderland, Mariana, Leung, Michelle, Escudero, Mickael, Angelova, Mihaela, Tanic, Miljana, Sivakumar, Monica, Kanu, Nnennaya, Chervova, Olga, Lucas, Olivia, Al-Sawaf, Othman, Hobson, Philip, Pawlik, Piotr, Bentham, Robert, Hynds, Robert E, Vendramin, Roberto, Saghafinia, Sadegh, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Vanloo, Sharon, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Marafioti, Teresa, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Liu, Wing Kin, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Borg, Elaine, Wilson, James, Patrini, Davide, Martinoni Hoogenboom, Emilie, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, Lim, Eric, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Nicholson, Andrew G, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Hewish, Madeleine, Danson, Sarah, Shackcloth, Michael J, Robinson, Lily, Russell, Peter, Dick, Craig, Le Quesne, John, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
Clonal Evolution, Cohort Studies, Evolution, Molecular, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Disease Progression, Humans, Neoplasm Metastasis, Neoplasm Recurrence, Local, Clone Cells
Abstract

Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse. ispartof: NATURE vol:616 issue:7957 ispartof: location:England status: Published online

Published
2023

24. The evolution of lung cancer and impact of subclonal selection in TRACERx

Author

Frankell, Alexander M, Dietzen, Michelle, Al Bakir, Maise, Lim, Emilia L, Karasaki, Takahiro, Ward, Sophia, Veeriah, Selvaraju, Colliver, Emma, Huebner, Ariana, Bunkum, Abigail, Hill, Mark S, Grigoriadis, Kristiana, Moore, David A, Black, James RM, Liu, Wing Kin, Thol, Kerstin, Pich, Oriol, Watkins, Thomas BK, Naceur-Lombardelli, Cristina, Cook, Daniel E, Salgado, Roberto, Wilson, Gareth A, Bailey, Chris, Angelova, Mihaela, Bentham, Robert, Martinez-Ruiz, Carlos, Abbosh, Christopher, Nicholson, Andrew G, Le Quesne, John, Biswas, Dhruva, Rosenthal, Rachel, Puttick, Clare, Hessey, Sonya, Lee, Claudia, Prymas, Paulina, Toncheva, Antonia, Smith, Jon, Xing, Wei, Nicod, Jerome, Price, Gillian, Kerr, Keith M, Naidu, Babu, Middleton, Gary, Blyth, Kevin G, Fennell, Dean A, Forster, Martin D, Lee, Siow Ming, Falzon, Mary, Hewish, Madeleine, Shackcloth, Michael J, Lim, Eric, Benafif, Sarah, Russell, Peter, Boleti, Ekaterini, Krebs, Matthew G, Lester, Jason F, Papadatos-Pastos, Dionysis, Ahmad, Tanya, Thakrar, Ricky M, Lawrence, David, Navani, Neal, Janes, Sam M, Dive, Caroline, Blackhall, Fiona H, Summers, Yvonne, Cave, Judith, Marafioti, Teresa, Herrero, Javier, Quezada, Sergio A, Peggs, Karl S, Schwarz, Roland F, Van Loo, Peter, Miedema, Daniel M, Birkbak, Nicolai J, Hiley, Crispin T, Hackshaw, Allan, Zaccaria, Simone, Jamal-Hanjani, Mariam, McGranahan, Nicholas, Swanton, Charles, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joa, Primrose, Lindsay, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Gilbert, Kayleigh, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Lindsay, Colin R, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Aerts, Hugo JWL, Kaufmann, Tom L, Szallasi, Zoltan, Kisistok, Judit, Sokac, Mateo, Diossy, Miklos, Demeulemeester, Jonas, Stewart, Aengus, Magness, Alastair, Rowan, Andrew, Karamani, Angeliki, Chain, Benny, Campbell, Brittany B, Castignani, Carla, Weeden, Clare E, Richard, Corentin, Pearce, David R, Karagianni, Despoina, Levi, Dina, Hoxha, Elena, Larose Cadieux, Elizabeth, Nye, Emma, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Gimeno-Valiente, Francisco, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Zhai, Haoran L, Lowe, Helen L, Matos, Ignacio, Goldman, Jacki, Reading, James L, Rane, Jayant K, Lam, Jie Min, Hartley, John A, Enfield, Katey SS, Selvaraju, Kayalvizhi, Litchfield, Kevin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Vasquez, Marcos, Litovchenko, Maria, Werner Sunderland, Mariana, Leung, Michelle, Escudero, Mickael, Tanic, Miljana, Sivakumar, Monica, Kanu, Nnennaya, Chervova, Olga, Lucas, Olivia, Al-Sawaf, Othman, Hobson, Philip, Pawlik, Piotr, Stone, Richard Kevin, Hynds, Robert E, Vendramin, Roberto, Saghafinia, Sadegh, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Vanloo, Sharon, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Borg, Elaine, Wilson, James, Procter, Alexander James, Ahmed, Asia, Taylor, Magali N, Nair, Arjun, Patrini, Davide, Martinoni Hoogenboom, Emilie, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Danson, Sarah, Robinson, Lily, Dick, Craig, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
Lung Neoplasms, Treatment Outcome, DNA Copy Number Variations, Mutagenesis, Carcinoma, Non-Small-Cell Lung, Mutation, Smoking, Humans, Adenocarcinoma of Lung, Neoplasm Recurrence, Local, Phylogeny
Abstract

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource. ispartof: NATURE vol:616 issue:7957 ispartof: location:England status: Published online

Published
2023

25. Evolutionary characterization of lung adenocarcinoma morphology in TRACERx

Author

Karasaki, Takahiro, Moore, David A, Veeriah, Selvaraju, Naceur-Lombardelli, Cristina, Toncheva, Antonia, Magno, Neil, Ward, Sophia, Al Bakir, Maise, Watkins, Thomas BK, Grigoriadis, Kristiana, Huebner, Ariana, Hill, Mark S, Frankell, Alexander M, Abbosh, Christopher, Puttick, Clare, Zhai, Haoran, Gimeno-Valiente, Francisco, Saghafinia, Sadegh, Kanu, Nnennaya, Dietzen, Michelle, Pich, Oriol, Lim, Emilia L, Martinez-Ruiz, Carlos, Black, James RM, Biswas, Dhruva, Campbell, Brittany B, Lee, Claudia, Colliver, Emma, Enfield, Katey SS, Hessey, Sonya, Hiley, Crispin T, Zaccaria, Simone, Litchfield, Kevin, Birkbak, Nicolai J, Cadieux, Elizabeth Larose, Demeulemeester, Jonas, Van Loo, Peter, Adusumilli, Prasad R, Tan, Kay See, Cheema, Waseem, Sanchez-Vega, Francisco, Jones, David R, Rekhtman, Natasha, Travis, William D, Hackshaw, Allan, Marafioti, Teresa, Salgado, Roberto, Le Quesne, John, Nicholson, Andrew G, McGranahan, Nicholas, Swanton, Charles, Jamal-Hanjani, Mariam, Lester, Jason F, Bajaj, Amrita, Nakas, Apostolos, Sodha-Ramdeen, Azmina, Ang, Keng, Tufail, Mohamad, Chowdhry, Mohammed Fiyaz, Scotland, Molly, Boyles, Rebecca, Rathinam, Sridhar, Wilson, Claire, Marrone, Domenic, Dulloo, Sean, Fennell, Dean A, Matharu, Gurdeep, Shaw, Jacqui A, Riley, Joan, Primrose, Lindsay, Boleti, Ekaterini, Cheyne, Heather, Khalil, Mohammed, Richardson, Shirley, Cruickshank, Tracey, Price, Gillian, Kerr, Keith M, Benafif, Sarah, Gilbert, Kayleigh, Naidu, Babu, Patel, Akshay J, Osman, Aya, Lacson, Christer, Langman, Gerald, Shackleford, Helen, Djearaman, Madava, Kadiri, Salma, Middleton, Gary, Leek, Angela, Hodgkinson, Jack Davies, Totten, Nicola, Montero, Angeles, Smith, Elaine, Fontaine, Eustace, Granato, Felice, Doran, Helen, Novasio, Juliette, Rammohan, Kendadai, Joseph, Leena, Bishop, Paul, Shah, Rajesh, Moss, Stuart, Joshi, Vijay, Crosbie, Philip, Gomes, Fabio, Brown, Kate, Carter, Mathew, Chaturvedi, Anshuman, Priest, Lynsey, Oliveira, Pedro, Lindsay, Colin R, Blackhall, Fiona H, Krebs, Matthew G, Summers, Yvonne, Clipson, Alexandra, Tugwood, Jonathan, Kerr, Alastair, Rothwell, Dominic G, Kilgour, Elaine, Dive, Caroline, Aerts, Hugo JWL, Schwarz, Roland F, Kaufmann, Tom L, Wilson, Gareth A, Rosenthal, Rachel, Szallasi, Zoltan, Kisistok, Judit, Sokac, Mateo, Diossy, Miklos, Bunkum, Abigail, Stewart, Aengus, Magness, Alastair, Rowan, Andrew, Karamani, Angeliki, Chain, Benny, Castignani, Carla, Bailey, Chris, Weeden, Clare E, Richard, Corentin, Pearce, David R, Karagianni, Despoina, Levi, Dina, Hoxha, Elena, Nye, Emma, Gronroos, Eva, Galvez-Cancino, Felip, Athanasopoulou, Foteini, Kassiotis, George, Stavrou, Georgia, Mastrokalos, Gerasimos, Lowe, Helen L, Matos, Ignacio Garcia, Goldman, Jacki, Reading, James L, Herrero, Javier, Rane, Jayant K, Nicod, Jerome, Lam, Jie Min, Hartley, John A, Peggs, Karl S, Selvaraju, Kayalvizhi, Thol, Kerstin, Ng, Kevin W, Chen, Kezhong, Dijkstra, Krijn, Thakkar, Krupa, Ensell, Leah, Shah, Mansi, Duran, Marcos Vasquez, Litovchenko, Maria, Sunderland, Mariana Werner, Leung, Michelle, Escudero, Mickael, Angelova, Mihaela, Tanic, Miljana, Sivakumar, Monica, Chervova, Olga, Lucas, Olivia, Al-Sawaf, Othman, Prymas, Paulina, Hobson, Philip, Pawlik, Piotr, Stone, Richard Kevin, Bentham, Robert, Hynds, Robert E, Vendramin, Roberto, Lopez, Saioa, Gamble, Samuel, Ung, Seng Kuong Anakin, Quezada, Sergio A, Vanloo, Sharon, Boeing, Stefan, Beck, Stephan, Bola, Supreet Kaur, Denner, Tamara, Mourikis, Thanos P, Spanswick, Victoria, Barbe, Vittorio, Lu, Wei-Ting, Hill, William, Liu, Wing Kin, Wu, Yin, Naito, Yutaka, Ramsden, Zoe, Veiga, Catarina, Royle, Gary, Collins-Fekete, Charles-Antoine, Fraioli, Francesco, Ashford, Paul, Clark, Tristan, Forster, Martin D, Lee, Siow Ming, Borg, Elaine, Falzon, Mary, Papadatos-Pastos, Dionysis, Wilson, James, Ahmad, Tanya, Procter, Alexander James, Ahmed, Asia, Taylor, Magali N, Nair, Arjun, Lawrence, David, Patrini, Davide, Navani, Neal, Thakrar, Ricky M, Janes, Sam M, Hoogenboom, Emilie Martinoni, Monk, Fleur, Holding, James W, Choudhary, Junaid, Bhakhri, Kunal, Scarci, Marco, Hayward, Martin, Panagiotopoulos, Nikolaos, Gorman, Pat, Khiroya, Reena, Stephens, Robert CM, Wong, Yien Ning Sophia, Bandula, Steve, Sharp, Abigail, Smith, Sean, Gower, Nicole, Dhanda, Harjot Kaur, Chan, Kitty, Pilotti, Camilla, Leslie, Rachel, Grapa, Anca, Zhang, Hanyun, AbdulJabbar, Khalid, Pan, Xiaoxi, Yuan, Yinyin, Chuter, David, MacKenzie, Mairead, Chee, Serena, Alzetani, Aiman, Cave, Judith, Scarlett, Lydia, Richards, Jennifer, Ingram, Papawadee, Austin, Silvia, Lim, Eric, De Sousa, Paulo, Jordan, Simon, Rice, Alexandra, Raubenheimer, Hilgardt, Bhayani, Harshil, Ambrose, Lyn, Devaraj, Anand, Chavan, Hema, Begum, Sofina, Buderi, Silviu, Kaniu, Daniel, Malima, Mpho, Booth, Sarah, Fernandes, Nadia, Shah, Pratibha, Proli, Chiara, Hewish, Madeleine, Danson, Sarah, Shackcloth, Michael J, Robinson, Lily, Russell, Peter, Blyth, Kevin G, Dick, Craig, Kirk, Alan, Asif, Mo, Bilancia, Rocco, Kostoulas, Nikos, and Thomas, Mathew

Subjects
TRACERx Consortium
Abstract

Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly high-grade pattern tumors exhibited higher proliferation and lower clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade tumors, while purely undifferentiated solid-pattern tumors had a higher frequency of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumors tend to evolve toward higher-grade patterns. The presence of micropapillary pattern and 'tumor spread through air spaces' were associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform patterns, necrosis and preoperative circulating tumor DNA detection, which were associated with extra-thoracic recurrence. These data provide insights into the relationship between LUAD morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk. ispartof: NATURE MEDICINE vol:29 issue:4 ispartof: location:United States status: Published online

Published
2023

26. Supplementary File 2 from A Phase Ib Open-Label Multicenter Study of AZD4547 in Patients with Advanced Squamous Cell Lung Cancers

Author

Paik, Paul K., primary, Shen, Ronglai, primary, Berger, Michael F., primary, Ferry, David, primary, Soria, Jean-Charles, primary, Mathewson, Alastair, primary, Rooney, Claire, primary, Smith, Neil R., primary, Cullberg, Marie, primary, Kilgour, Elaine, primary, Landers, Donal, primary, Frewer, Paul, primary, Brooks, Nigel, primary, and André, Fabrice, primary

Published
2023
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27. Supplementary File 1 from A Phase Ib Open-Label Multicenter Study of AZD4547 in Patients with Advanced Squamous Cell Lung Cancers

Author

Paik, Paul K., primary, Shen, Ronglai, primary, Berger, Michael F., primary, Ferry, David, primary, Soria, Jean-Charles, primary, Mathewson, Alastair, primary, Rooney, Claire, primary, Smith, Neil R., primary, Cullberg, Marie, primary, Kilgour, Elaine, primary, Landers, Donal, primary, Frewer, Paul, primary, Brooks, Nigel, primary, and André, Fabrice, primary

Published
2023
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28. Supplementary File 5 from A Phase Ib Open-Label Multicenter Study of AZD4547 in Patients with Advanced Squamous Cell Lung Cancers

Author

Paik, Paul K., primary, Shen, Ronglai, primary, Berger, Michael F., primary, Ferry, David, primary, Soria, Jean-Charles, primary, Mathewson, Alastair, primary, Rooney, Claire, primary, Smith, Neil R., primary, Cullberg, Marie, primary, Kilgour, Elaine, primary, Landers, Donal, primary, Frewer, Paul, primary, Brooks, Nigel, primary, and André, Fabrice, primary

Published
2023
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29. Supplementary Figure 1 from Translating the Therapeutic Potential of AZD4547 in FGFR1-Amplified Non–Small Cell Lung Cancer through the Use of Patient-Derived Tumor Xenograft Models

Author

Zhang, Jingchuan, primary, Zhang, Lin, primary, Su, Xinying, primary, Li, Ming, primary, Xie, Liang, primary, Malchers, Florian, primary, Fan, ShuQiong, primary, Yin, XiaoLu, primary, Xu, YanPing, primary, Liu, Kunji, primary, Dong, Zhengwei, primary, Zhu, Guanshan, primary, Qian, Ziliang, primary, Tang, Lili, primary, Zhan, Ping, primary, Ji, Qunsheng, primary, Kilgour, Elaine, primary, Smith, Paul D., primary, Brooks, A. Nigel, primary, Thomas, Roman K., primary, and Gavine, Paul R., primary

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2023
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30. Supplementary Figure 2 from Translating the Therapeutic Potential of AZD4547 in FGFR1-Amplified Non–Small Cell Lung Cancer through the Use of Patient-Derived Tumor Xenograft Models

Author

Zhang, Jingchuan, primary, Zhang, Lin, primary, Su, Xinying, primary, Li, Ming, primary, Xie, Liang, primary, Malchers, Florian, primary, Fan, ShuQiong, primary, Yin, XiaoLu, primary, Xu, YanPing, primary, Liu, Kunji, primary, Dong, Zhengwei, primary, Zhu, Guanshan, primary, Qian, Ziliang, primary, Tang, Lili, primary, Zhan, Ping, primary, Ji, Qunsheng, primary, Kilgour, Elaine, primary, Smith, Paul D., primary, Brooks, A. Nigel, primary, Thomas, Roman K., primary, and Gavine, Paul R., primary

Published
2023
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31. Supplementary File 3 from A Phase Ib Open-Label Multicenter Study of AZD4547 in Patients with Advanced Squamous Cell Lung Cancers

Author

Paik, Paul K., primary, Shen, Ronglai, primary, Berger, Michael F., primary, Ferry, David, primary, Soria, Jean-Charles, primary, Mathewson, Alastair, primary, Rooney, Claire, primary, Smith, Neil R., primary, Cullberg, Marie, primary, Kilgour, Elaine, primary, Landers, Donal, primary, Frewer, Paul, primary, Brooks, Nigel, primary, and André, Fabrice, primary

Published
2023
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32. Supplementary File 6 from A Phase Ib Open-Label Multicenter Study of AZD4547 in Patients with Advanced Squamous Cell Lung Cancers

Author

Paik, Paul K., primary, Shen, Ronglai, primary, Berger, Michael F., primary, Ferry, David, primary, Soria, Jean-Charles, primary, Mathewson, Alastair, primary, Rooney, Claire, primary, Smith, Neil R., primary, Cullberg, Marie, primary, Kilgour, Elaine, primary, Landers, Donal, primary, Frewer, Paul, primary, Brooks, Nigel, primary, and André, Fabrice, primary

Published
2023
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33. Supplementary Figure Legend from Translating the Therapeutic Potential of AZD4547 in FGFR1-Amplified Non–Small Cell Lung Cancer through the Use of Patient-Derived Tumor Xenograft Models

Author

Zhang, Jingchuan, primary, Zhang, Lin, primary, Su, Xinying, primary, Li, Ming, primary, Xie, Liang, primary, Malchers, Florian, primary, Fan, ShuQiong, primary, Yin, XiaoLu, primary, Xu, YanPing, primary, Liu, Kunji, primary, Dong, Zhengwei, primary, Zhu, Guanshan, primary, Qian, Ziliang, primary, Tang, Lili, primary, Zhan, Ping, primary, Ji, Qunsheng, primary, Kilgour, Elaine, primary, Smith, Paul D., primary, Brooks, A. Nigel, primary, Thomas, Roman K., primary, and Gavine, Paul R., primary

Published
2023
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34. Supplementary File 4 from A Phase Ib Open-Label Multicenter Study of AZD4547 in Patients with Advanced Squamous Cell Lung Cancers

Author

Paik, Paul K., primary, Shen, Ronglai, primary, Berger, Michael F., primary, Ferry, David, primary, Soria, Jean-Charles, primary, Mathewson, Alastair, primary, Rooney, Claire, primary, Smith, Neil R., primary, Cullberg, Marie, primary, Kilgour, Elaine, primary, Landers, Donal, primary, Frewer, Paul, primary, Brooks, Nigel, primary, and André, Fabrice, primary

Published
2023
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35. Supplementary Tables 1 - 4 from Translating the Therapeutic Potential of AZD4547 in FGFR1-Amplified Non–Small Cell Lung Cancer through the Use of Patient-Derived Tumor Xenograft Models

Author

Zhang, Jingchuan, primary, Zhang, Lin, primary, Su, Xinying, primary, Li, Ming, primary, Xie, Liang, primary, Malchers, Florian, primary, Fan, ShuQiong, primary, Yin, XiaoLu, primary, Xu, YanPing, primary, Liu, Kunji, primary, Dong, Zhengwei, primary, Zhu, Guanshan, primary, Qian, Ziliang, primary, Tang, Lili, primary, Zhan, Ping, primary, Ji, Qunsheng, primary, Kilgour, Elaine, primary, Smith, Paul D., primary, Brooks, A. Nigel, primary, Thomas, Roman K., primary, and Gavine, Paul R., primary

Published
2023
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36. Data from AZD4547: An Orally Bioavailable, Potent, and Selective Inhibitor of the Fibroblast Growth Factor Receptor Tyrosine Kinase Family

Author

Gavine, Paul R., primary, Mooney, Lorraine, primary, Kilgour, Elaine, primary, Thomas, Andrew P., primary, Al-Kadhimi, Katherine, primary, Beck, Sarah, primary, Rooney, Claire, primary, Coleman, Tanya, primary, Baker, Dawn, primary, Mellor, Martine J., primary, Brooks, A. Nigel, primary, and Klinowska, Teresa, primary

Published
2023
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37. Supplementary Table 1 from AZD4547: An Orally Bioavailable, Potent, and Selective Inhibitor of the Fibroblast Growth Factor Receptor Tyrosine Kinase Family

Author

Gavine, Paul R., primary, Mooney, Lorraine, primary, Kilgour, Elaine, primary, Thomas, Andrew P., primary, Al-Kadhimi, Katherine, primary, Beck, Sarah, primary, Rooney, Claire, primary, Coleman, Tanya, primary, Baker, Dawn, primary, Mellor, Martine J., primary, Brooks, A. Nigel, primary, and Klinowska, Teresa, primary

Published
2023
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38. Supplementary Figure Legends 1-2 from AZD4547: An Orally Bioavailable, Potent, and Selective Inhibitor of the Fibroblast Growth Factor Receptor Tyrosine Kinase Family

Author

Gavine, Paul R., primary, Mooney, Lorraine, primary, Kilgour, Elaine, primary, Thomas, Andrew P., primary, Al-Kadhimi, Katherine, primary, Beck, Sarah, primary, Rooney, Claire, primary, Coleman, Tanya, primary, Baker, Dawn, primary, Mellor, Martine J., primary, Brooks, A. Nigel, primary, and Klinowska, Teresa, primary

Published
2023
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39. Supplementary Figure 2 from AZD4547: An Orally Bioavailable, Potent, and Selective Inhibitor of the Fibroblast Growth Factor Receptor Tyrosine Kinase Family

Author

Gavine, Paul R., primary, Mooney, Lorraine, primary, Kilgour, Elaine, primary, Thomas, Andrew P., primary, Al-Kadhimi, Katherine, primary, Beck, Sarah, primary, Rooney, Claire, primary, Coleman, Tanya, primary, Baker, Dawn, primary, Mellor, Martine J., primary, Brooks, A. Nigel, primary, and Klinowska, Teresa, primary

Published
2023
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40. Supplementary Figure 1 from AZD4547: An Orally Bioavailable, Potent, and Selective Inhibitor of the Fibroblast Growth Factor Receptor Tyrosine Kinase Family

Author

Gavine, Paul R., primary, Mooney, Lorraine, primary, Kilgour, Elaine, primary, Thomas, Andrew P., primary, Al-Kadhimi, Katherine, primary, Beck, Sarah, primary, Rooney, Claire, primary, Coleman, Tanya, primary, Baker, Dawn, primary, Mellor, Martine J., primary, Brooks, A. Nigel, primary, and Klinowska, Teresa, primary

Published
2023
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41. Abstract 3098: The first circulating tumor cell-derived explant (CDX) model of a Merkel cell carcinoma

Author

Frizziero, Melissa, primary, Kilgour, Elaine, additional, Simpson, Kathryn L., additional, Rothwell, Dominic, additional, Frese, Kristopher, additional, Galvin, Melanie, additional, Chen, Yitao, additional, Kerr, Alastair, additional, Humphrey, Sam, additional, Hossain, Mukarram, additional, Valle, Juan W., additional, McNamara, Mairéad G., additional, and Dive, Caroline, additional

Published
2022
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42. Abstract 2808: cfDNA multi-omics profiling and tissue of origin predictions in cancers of unknown primary

Author

Conway, Alicia-Marie, primary, Clipson, Alexandra, additional, Chemi, Francesca, additional, Pearce, Simon, additional, Kamieniecka, Katarzyna, additional, Ferdous, Saba, additional, Richardson, Sophie, additional, Kilgour, Elaine, additional, Krebs, Matthew G., additional, Kerr, Alastair, additional, Rothwell, Dominic, additional, Cook, Natalie, additional, and Dive, Caroline, additional

Published
2022
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44. Expanding Therapeutic Opportunities for Extrapulmonary Neuroendocrine Carcinoma

Author

Frizziero, Melissa, primary, Kilgour, Elaine, additional, Simpson, Kathryn L., additional, Rothwell, Dominic G., additional, Moore, David A., additional, Frese, Kristopher K., additional, Galvin, Melanie, additional, Lamarca, Angela, additional, Hubner, Richard A., additional, Valle, Juan W., additional, McNamara, Mairéad G., additional, and Dive, Caroline, additional

Published
2022
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45. Glucagon activates two distinct signal transduction systems in hepatocytes, which leads to the desensitization of G-protein-regulated adenylate cyclase, the phosphorylation and inactivation of Gi-2 and the phosphorylation and stimulation of a specific cyclic AMP phosphodiesterase

Author

Houslay, Miles D., Bushfield, Mark, Kilgour, Elaine, Lavan, Brian, Griffiths, Suzanne, Pyne, Nigel J., Tang, Eric K.-Y., Murphy, Gregory J., Konijn, T. M., editor, Houslay, M. D., editor, and Van Haastert, P. J. M., editor

Published
1990
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46. Serial monitoring of genomic alterations in circulating tumor cells of ER‐positive/HER2‐negative advanced breast cancer: feasibility of precision oncology biomarker detection

Author

Cani, Andi K., primary, Dolce, Emily M., additional, Darga, Elizabeth P., additional, Hu, Kevin, additional, Liu, Chia‐Jen, additional, Pierce, Jackie, additional, Bradbury, Kieran, additional, Kilgour, Elaine, additional, Aung, Kimberly, additional, Schiavon, Gaia, additional, Carroll, Danielle, additional, Carr, T. Hedley, additional, Klinowska, Teresa, additional, Lindemann, Justin, additional, Marshall, Gayle, additional, Rowlands, Vicky, additional, Harrington, Elizabeth A., additional, Barrett, J. Carl, additional, Sathiyayogan, Nitharsan, additional, Morrow, Christopher, additional, Sero, Valeria, additional, Armstrong, Anne C., additional, Baird, Richard, additional, Hamilton, Erika, additional, Im, Seock‐Ah, additional, Jhaveri, Komal, additional, Patel, Manish R., additional, Dive, Caroline, additional, Tomlins, Scott A., additional, Udager, Aaron M., additional, Hayes, Daniel F., additional, and Paoletti, Costanza, additional

Published
2021
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50. Molecular characterisation and liquid biomarkers in Carcinoma of Unknown Primary (CUP): taking the ‘U’ out of ‘CUP’

Author

Conway, Alicia-Marie, Mitchell, Claire, Kilgour, Elaine, Brady, Gerard, Dive, Caroline, and Cook, Natalie

Subjects
Liquid biopsy, Manchester Cancer Research Centre, ResearchInstitutes_Networks_Beacons/mcrc, Carcinoma, Review Article, Prognosis, Cancer of Unknown Primary, Cancer of unknown primary, Tumour biomarkers, Gene Expression Regulation, Neoplastic, Cancer genomics, Biomarkers, Tumor, Humans, Neoplasms, Unknown Primary, Tissue-of-Origin, Precision Medicine
Abstract

Cancers of Unknown Primary (CUP) comprise a heterogeneous clinical entity of confirmed metastatic cancer where the primary site of origin is undetectable. It has a poor prognosis with limited treatment options. CUP is historically under-researched; however, understanding its biology has the potential to not only improve treatment and survival by implementation of biomarkers for patient management, but also to greatly contribute to our understanding of carcinogenesis and metastasis across all cancer types. Here we review the current advances in CUP research and explore the debated hypotheses underlying its biology. The evolution of molecular profiling and tissue-of-origin classifiers have the potential to transform the diagnosis, classification and therapeutic management of patients with CUP but robust evidence to support widespread use is lacking. Precision medicine has transformed treatment strategy in known tumour types; in CUP, however, there remains a clinical need for a better understanding of molecular characteristics to establish the potential role of novel or existing therapeutics. The emergence of liquid biopsies as a source of predictive and prognostic biomarkers within known tumour types is gaining rapid ground and this review explores the potential utility of liquid biopsies in CUP.

Published
2018
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