135 results on '"Frankell, A"'
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2. Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling
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Sebastijan Hobor, Maise Al Bakir, Crispin T. Hiley, Marcin Skrzypski, Alexander M. Frankell, Bjorn Bakker, Thomas B. K. Watkins, Aleksandra Markovets, Jonathan R. Dry, Andrew P. Brown, Jasper van der Aart, Hilda van den Bos, Diana Spierings, Dahmane Oukrif, Marco Novelli, Turja Chakrabarti, Adam H. Rabinowitz, Laila Ait Hassou, Saskia Litière, D. Lucas Kerr, Lisa Tan, Gavin Kelly, David A. Moore, Matthew J. Renshaw, Subramanian Venkatesan, William Hill, Ariana Huebner, Carlos Martínez-Ruiz, James R. M. Black, Wei Wu, Mihaela Angelova, Nicholas McGranahan, Julian Downward, Juliann Chmielecki, Carl Barrett, Kevin Litchfield, Su Kit Chew, Collin M. Blakely, Elza C. de Bruin, Floris Foijer, Karen H. Vousden, Trever G. Bivona, TRACERx consortium, Robert E. Hynds, Nnennaya Kanu, Simone Zaccaria, Eva Grönroos, and Charles Swanton
- Subjects
Science - Abstract
Abstract The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.
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- 2024
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3. CONIPHER: a computational framework for scalable phylogenetic reconstruction with error correction
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Grigoriadis, Kristiana, Huebner, Ariana, Bunkum, Abigail, Colliver, Emma, Frankell, Alexander M., Hill, Mark S., Thol, Kerstin, Birkbak, Nicolai J., Swanton, Charles, Zaccaria, Simone, and McGranahan, Nicholas
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- 2024
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4. Author Correction: The evolution of lung cancer and impact of subclonal selection in TRACERx
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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 R. M., Liu, Wing Kin, Thol, Kerstin, Pich, Oriol, Watkins, Thomas B. K., Naceur-Lombardelli, Cristina, Cook, Daniel E., Salgado, Roberto, Wilson, Gareth A., Bailey, Chris, Angelova, Mihaela, Bentham, Robert, Martínez-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, Daniël M., Birkbak, Nicolai J., Hiley, Crispin T., Hackshaw, Allan, Zaccaria, Simone, Jamal-Hanjani, Mariam, McGranahan, Nicholas, and Swanton, Charles
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- 2024
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5. Antibodies against endogenous retroviruses promote lung cancer immunotherapy
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Ng, Kevin W., Boumelha, Jesse, Enfield, Katey S. S., Almagro, Jorge, Cha, Hongui, Pich, Oriol, Karasaki, Takahiro, Moore, David A., Salgado, Roberto, Sivakumar, Monica, Young, George, Molina-Arcas, Miriam, de Carné Trécesson, Sophie, Anastasiou, Panayiotis, Fendler, Annika, Au, Lewis, Shepherd, Scott T. C., Martínez-Ruiz, Carlos, Puttick, Clare, Black, James R. M., Watkins, Thomas B. K., Kim, Hyemin, Shim, Seohee, Faulkner, Nikhil, Attig, Jan, Veeriah, Selvaraju, Magno, Neil, Ward, Sophia, Frankell, Alexander M., Al Bakir, Maise, Lim, Emilia L., Hill, Mark S., Wilson, Gareth A., Cook, Daniel E., Birkbak, Nicolai J., Behrens, Axel, Yousaf, Nadia, Popat, Sanjay, Hackshaw, Allan, Hiley, Crispin T., Litchfield, Kevin, McGranahan, Nicholas, Jamal-Hanjani, Mariam, Larkin, James, Lee, Se-Hoon, Turajlic, Samra, Swanton, Charles, Downward, Julian, and Kassiotis, George
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- 2023
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6. The evolution of non-small cell lung cancer metastases in TRACERx
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Al Bakir, Maise, Huebner, Ariana, Martínez-Ruiz, Carlos, Grigoriadis, Kristiana, Watkins, Thomas B. K., 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 M., 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 A., Peggs, Karl S., Van Loo, Peter, Dive, Caroline, Hackshaw, Allan, Birkbak, Nicolai J., Zaccaria, Simone, Jamal-Hanjani, Mariam, McGranahan, Nicholas, and Swanton, Charles
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- 2023
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7. The evolution of lung cancer and impact of subclonal selection in TRACERx
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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 R. M., Liu, Wing Kin, Thol, Kerstin, Pich, Oriol, Watkins, Thomas B. K., Naceur-Lombardelli, Cristina, Cook, Daniel E., Salgado, Roberto, Wilson, Gareth A., Bailey, Chris, Angelova, Mihaela, Bentham, Robert, Martínez-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, Daniël M., Birkbak, Nicolai J., Hiley, Crispin T., Hackshaw, Allan, Zaccaria, Simone, Jamal-Hanjani, Mariam, McGranahan, Nicholas, and Swanton, Charles
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- 2023
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8. Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA
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Abbosh, Christopher, Frankell, Alexander M., Harrison, Thomas, Kisistok, Judit, Garnett, Aaron, Johnson, Laura, Veeriah, Selvaraju, Moreau, Mike, Chesh, Adrian, Chaunzwa, Tafadzwa L., Weiss, Jakob, Schroeder, Morgan R., Ward, Sophia, Grigoriadis, Kristiana, Shahpurwalla, Aamir, Litchfield, Kevin, Puttick, Clare, Biswas, Dhruva, Karasaki, Takahiro, Black, James R. M., Martínez-Ruiz, Carlos, Bakir, Maise Al, Pich, Oriol, Watkins, Thomas B. K., Lim, Emilia L., Huebner, Ariana, Moore, David A., Godin-Heymann, Nadia, L’Hernault, Anne, Bye, Hannah, Odell, Aaron, Roberts, Paula, Gomes, Fabio, Patel, Akshay J., Manzano, Elizabeth, Hiley, Crispin T., Carey, Nicolas, Riley, Joan, Cook, Daniel E., Hodgson, Darren, Stetson, Daniel, Barrett, J. Carl, Kortlever, Roderik M., Evan, Gerard I., Hackshaw, Allan, Daber, Robert D., Shaw, Jacqui A., Aerts, Hugo J. W. L., Licon, Abel, Stahl, Josh, Jamal-Hanjani, Mariam, Birkbak, Nicolai J., McGranahan, Nicholas, and Swanton, Charles
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- 2023
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9. Genomic–transcriptomic evolution in lung cancer and metastasis
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Martínez-Ruiz, Carlos, Black, James R. M., Puttick, Clare, Hill, Mark S., Demeulemeester, Jonas, Larose Cadieux, Elizabeth, Thol, Kerstin, Jones, Thomas P., Veeriah, Selvaraju, Naceur-Lombardelli, Cristina, Toncheva, Antonia, Prymas, Paulina, Rowan, Andrew, Ward, Sophia, Cubitt, Laura, Athanasopoulou, Foteini, Pich, Oriol, Karasaki, Takahiro, Moore, David A., Salgado, Roberto, Colliver, Emma, Castignani, Carla, Dietzen, Michelle, Huebner, Ariana, Al Bakir, Maise, Tanić, Miljana, Watkins, Thomas B. K., Lim, Emilia L., Al-Rashed, Ali M., Lang, Danny, Clements, James, Cook, Daniel E., Rosenthal, Rachel, Wilson, Gareth A., Frankell, Alexander M., de Carné Trécesson, Sophie, East, Philip, Kanu, Nnennaya, Litchfield, Kevin, Birkbak, Nicolai J., Hackshaw, Allan, Beck, Stephan, Van Loo, Peter, Jamal-Hanjani, Mariam, Swanton, Charles, and McGranahan, Nicholas
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- 2023
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10. Evolutionary characterization of lung adenocarcinoma morphology in TRACERx
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Karasaki, Takahiro, Moore, David A., Veeriah, Selvaraju, Naceur-Lombardelli, Cristina, Toncheva, Antonia, Magno, Neil, Ward, Sophia, Bakir, Maise Al, Watkins, Thomas B. K., 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., Martínez-Ruiz, Carlos, Black, James R. M., Biswas, Dhruva, Campbell, Brittany B., Lee, Claudia, Colliver, Emma, Enfield, Katey S. S., Hessey, Sonya, Hiley, Crispin T., Zaccaria, Simone, Litchfield, Kevin, Birkbak, Nicolai J., Cadieux, Elizabeth Larose, Demeulemeester, Jonas, Van Loo, Peter, Adusumilli, Prasad S., 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, and Jamal-Hanjani, Mariam
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- 2023
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11. Body composition and lung cancer-associated cachexia in TRACERx
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Al-Sawaf, Othman, Weiss, Jakob, Skrzypski, Marcin, Lam, Jie Min, Karasaki, Takahiro, Zambrana, Francisco, Kidd, Andrew C., Frankell, Alexander M., Watkins, Thomas B. K., Martínez-Ruiz, Carlos, Puttick, Clare, Black, James R. M., Huebner, Ariana, Bakir, Maise Al, Sokač, 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 J. W. L., Jamal-Hanjani, Mariam, and Swanton, Charles
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- 2023
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12. Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling
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Hobor, S, Al Bakir, M, Hiley, C, Skrzypski, M, Frankell, A, Bakker, B, Watkins, T, Markovets, A, Dry, J, Brown, A, van der Aart, J, van den Bos, H, Spierings, D, Oukrif, D, Novelli, M, Chakrabarti, T, Rabinowitz, A, Ait Hassou, L, Litiere, S, Kerr, D, Tan, L, Kelly, G, Moore, D, Renshaw, M, Venkatesan, S, Hill, W, Huebner, A, Martinez-Ruiz, C, Black, J, Wu, W, Angelova, M, Mcgranahan, N, Downward, J, Chmielecki, J, Barrett, C, Litchfield, K, Chew, S, Blakely, C, de Bruin, E, Foijer, F, Vousden, K, Bivona, T, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Tufail, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Shaw, J, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, French, J, Gilbert, K, Naidu, B, Patel, A, Osman, A, Enstone, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totton, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Paiva-Correia, A, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Brown, K, Carter, M, Chaturvedi, A, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Dive, C, Aerts, H, Schwarz, R, Kaufmann, T, Wilson, G, Rosenthal, R, Van Loo, P, Birkbak, N, Szallasi, Z, Kisistok, J, Sokac, M, Salgado, R, Diossy, M, Demeulemeester, J, Bunkum, A, Dwornik, A, Magness, A, Rowan, A, Karamani, A, Toncheva, A, Chain, B, Castignani, C, Bailey, C, Abbosh, C, Puttick, C, Weeden, C, Lee, C, Richard, C, Naceur-Lombardelli, C, Pearce, D, Karagianni, D, Biswas, D, Levi, D, Larose Cadieux, E, Lim, E, Colliver, E, Nye, E, Galvez-Cancino, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Lowe, H, Matos, I, Noorani, I, Goldman, J, Reading, J, Rane, J, Nicod, J, Hartley, J, Peggs, K, Enfield, K, Selvaraju, K, Thol, K, Ng, K, Chen, K, Dijkstra, K, Grigoriadis, K, Thakkar, K, Ensell, L, Shah, M, Litovchenko, M, Jamal-Hanjani, M, Werner Sunderland, M, Huska, M, Hill, M, Dietzen, M, Leung, M, Escudero, M, Tanic, M, Sivakumar, M, Chervova, O, Lucas, O, Pich, O, Al-Sawaf, O, Prymas, P, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Vendramin, R, Saghafinia, S, Gamble, S, Veeriah, S, Ung, S, Quezada, S, Vanloo, S, Hessey, S, Ward, S, Harries, S, Boeing, S, Beck, S, Bola, S, Karasaki, T, Denner, T, Marafioti, T, Jones, T, Spanswick, V, Barbe, V, Lu, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Martinoni Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Kaplar, Z, Bandula, S, Hackshaw, A, Hacker, A, Sharp, A, Smith, S, Kaur Dhanda, H, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Richards, J, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Nicholson, A, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Kidd, A, Dick, C, Le Quesne, J, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Hynds, R, Kanu, N, Zaccaria, S, Gronroos, E, Swanton, C, Hobor S., Al Bakir M., Hiley C. T., Skrzypski M., Frankell A. M., Bakker B., Watkins T. B. K., Markovets A., Dry J. R., Brown A. P., van der Aart J., van den Bos H., Spierings D., Oukrif D., Novelli M., Chakrabarti T., Rabinowitz A. H., Ait Hassou L., Litiere S., Kerr D. L., Tan L., Kelly G., Moore D. A., Renshaw M. J., Venkatesan S., Hill W., Huebner A., Martinez-Ruiz C., Black J. R. M., Wu W., Angelova M., McGranahan N., Downward J., Chmielecki J., Barrett C., Litchfield K., Chew S. K., Blakely C. M., de Bruin E. C., Foijer F., Vousden K. H., Bivona T. G., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Tufail M., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Shaw J. A., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., French J., Gilbert K., Naidu B., Patel A. J., Osman A., Enstone C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totton N., Montero A., Smith E., Fontaine E., Granato F., Paiva-Correia A., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P. A. J., Brown K. D., Carter M., Chaturvedi A., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Dive C., Aerts H. J. W. L., Schwarz R. F., Kaufmann T. L., Wilson G. A., Rosenthal R., Van Loo P., Birkbak N. J., Szallasi Z., Kisistok J., Sokac M., Salgado R., Diossy M., Demeulemeester J., Bunkum A., Dwornik A., Magness A., Rowan A. J., Karamani A., Toncheva A., Chain B., Castignani C., Bailey C., Abbosh C., Puttick C., Weeden C. E., Lee C., Richard C., Naceur-Lombardelli C., Pearce D. R., Karagianni D., Biswas D., Levi D., Larose Cadieux E., Lim E. L., Colliver E., Nye E., Galvez-Cancino F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G. -T., Lowe H. L., Matos I. G., Noorani I., Goldman J., Reading J. L., Rane J. K., Nicod J., Hartley J. A., Peggs K. S., Enfield K. S. S., Selvaraju K., Thol K., Ng K. W., Chen K., Dijkstra K., Grigoriadis K., Thakkar K., Ensell L., Shah M., Litovchenko M., Jamal-Hanjani M., Werner Sunderland M., Huska M. R., Hill M. S., Dietzen M., Leung M. M., Escudero M., Tanic M., Sivakumar M., Chervova O., Lucas O., Pich O., Al-Sawaf O., Prymas P., Hobson P., Pawlik P., Stone R. K., Bentham R., Vendramin R., Saghafinia S., Gamble S., Veeriah S., Ung S. K. A., Quezada S. A., Vanloo S., Hessey S., Ward S., Harries S., Boeing S., Beck S., Bola S. K., Karasaki T., Denner T., Marafioti T., Jones T. P., Spanswick V., Barbe V., Lu W. -T., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Martinoni Hoogenboom E., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Gorman P., Khiroya R., Stephens R. C. M., Wong Y. N. S., Kaplar Z., Bandula S., Hackshaw A., Hacker A. -M., Sharp A., Smith S., Kaur Dhanda H., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Richards J., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Nicholson A. G., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Kidd A., Dick C., Le Quesne J., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Hynds R. E., Kanu N., Zaccaria S., Gronroos E., Swanton C., Hobor, S, Al Bakir, M, Hiley, C, Skrzypski, M, Frankell, A, Bakker, B, Watkins, T, Markovets, A, Dry, J, Brown, A, van der Aart, J, van den Bos, H, Spierings, D, Oukrif, D, Novelli, M, Chakrabarti, T, Rabinowitz, A, Ait Hassou, L, Litiere, S, Kerr, D, Tan, L, Kelly, G, Moore, D, Renshaw, M, Venkatesan, S, Hill, W, Huebner, A, Martinez-Ruiz, C, Black, J, Wu, W, Angelova, M, Mcgranahan, N, Downward, J, Chmielecki, J, Barrett, C, Litchfield, K, Chew, S, Blakely, C, de Bruin, E, Foijer, F, Vousden, K, Bivona, T, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Tufail, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Shaw, J, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, French, J, Gilbert, K, Naidu, B, Patel, A, Osman, A, Enstone, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totton, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Paiva-Correia, A, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Brown, K, Carter, M, Chaturvedi, A, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Dive, C, Aerts, H, Schwarz, R, Kaufmann, T, Wilson, G, Rosenthal, R, Van Loo, P, Birkbak, N, Szallasi, Z, Kisistok, J, Sokac, M, Salgado, R, Diossy, M, Demeulemeester, J, Bunkum, A, Dwornik, A, Magness, A, Rowan, A, Karamani, A, Toncheva, A, Chain, B, Castignani, C, Bailey, C, Abbosh, C, Puttick, C, Weeden, C, Lee, C, Richard, C, Naceur-Lombardelli, C, Pearce, D, Karagianni, D, Biswas, D, Levi, D, Larose Cadieux, E, Lim, E, Colliver, E, Nye, E, Galvez-Cancino, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Lowe, H, Matos, I, Noorani, I, Goldman, J, Reading, J, Rane, J, Nicod, J, Hartley, J, Peggs, K, Enfield, K, Selvaraju, K, Thol, K, Ng, K, Chen, K, Dijkstra, K, Grigoriadis, K, Thakkar, K, Ensell, L, Shah, M, Litovchenko, M, Jamal-Hanjani, M, Werner Sunderland, M, Huska, M, Hill, M, Dietzen, M, Leung, M, Escudero, M, Tanic, M, Sivakumar, M, Chervova, O, Lucas, O, Pich, O, Al-Sawaf, O, Prymas, P, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Vendramin, R, Saghafinia, S, Gamble, S, Veeriah, S, Ung, S, Quezada, S, Vanloo, S, Hessey, S, Ward, S, Harries, S, Boeing, S, Beck, S, Bola, S, Karasaki, T, Denner, T, Marafioti, T, Jones, T, Spanswick, V, Barbe, V, Lu, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Martinoni Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Kaplar, Z, Bandula, S, Hackshaw, A, Hacker, A, Sharp, A, Smith, S, Kaur Dhanda, H, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Richards, J, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Nicholson, A, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Kidd, A, Dick, C, Le Quesne, J, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Hynds, R, Kanu, N, Zaccaria, S, Gronroos, E, Swanton, C, Hobor S., Al Bakir M., Hiley C. T., Skrzypski M., Frankell A. M., Bakker B., Watkins T. B. K., Markovets A., Dry J. R., Brown A. P., van der Aart J., van den Bos H., Spierings D., Oukrif D., Novelli M., Chakrabarti T., Rabinowitz A. H., Ait Hassou L., Litiere S., Kerr D. L., Tan L., Kelly G., Moore D. A., Renshaw M. J., Venkatesan S., Hill W., Huebner A., Martinez-Ruiz C., Black J. R. M., Wu W., Angelova M., McGranahan N., Downward J., Chmielecki J., Barrett C., Litchfield K., Chew S. K., Blakely C. M., de Bruin E. C., Foijer F., Vousden K. H., Bivona T. G., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Tufail M., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Shaw J. A., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., French J., Gilbert K., Naidu B., Patel A. J., Osman A., Enstone C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totton N., Montero A., Smith E., Fontaine E., Granato F., Paiva-Correia A., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P. A. J., Brown K. D., Carter M., Chaturvedi A., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Dive C., Aerts H. J. W. L., Schwarz R. F., Kaufmann T. L., Wilson G. A., Rosenthal R., Van Loo P., Birkbak N. J., Szallasi Z., Kisistok J., Sokac M., Salgado R., Diossy M., Demeulemeester J., Bunkum A., Dwornik A., Magness A., Rowan A. J., Karamani A., Toncheva A., Chain B., Castignani C., Bailey C., Abbosh C., Puttick C., Weeden C. E., Lee C., Richard C., Naceur-Lombardelli C., Pearce D. R., Karagianni D., Biswas D., Levi D., Larose Cadieux E., Lim E. L., Colliver E., Nye E., Galvez-Cancino F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G. -T., Lowe H. L., Matos I. G., Noorani I., Goldman J., Reading J. L., Rane J. K., Nicod J., Hartley J. A., Peggs K. S., Enfield K. S. S., Selvaraju K., Thol K., Ng K. W., Chen K., Dijkstra K., Grigoriadis K., Thakkar K., Ensell L., Shah M., Litovchenko M., Jamal-Hanjani M., Werner Sunderland M., Huska M. R., Hill M. S., Dietzen M., Leung M. M., Escudero M., Tanic M., Sivakumar M., Chervova O., Lucas O., Pich O., Al-Sawaf O., Prymas P., Hobson P., Pawlik P., Stone R. K., Bentham R., Vendramin R., Saghafinia S., Gamble S., Veeriah S., Ung S. K. A., Quezada S. A., Vanloo S., Hessey S., Ward S., Harries S., Boeing S., Beck S., Bola S. K., Karasaki T., Denner T., Marafioti T., Jones T. P., Spanswick V., Barbe V., Lu W. -T., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Martinoni Hoogenboom E., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Gorman P., Khiroya R., Stephens R. C. M., Wong Y. N. S., Kaplar Z., Bandula S., Hackshaw A., Hacker A. -M., Sharp A., Smith S., Kaur Dhanda H., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Richards J., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Nicholson A. G., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Kidd A., Dick C., Le Quesne J., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Hynds R. E., Kanu N., Zaccaria S., Gronroos E., and Swanton C.
- Abstract
The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.
- Published
- 2024
13. The artificial intelligence-based model ANORAK improves histopathological grading of lung adenocarcinoma
- Author
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Pan, X, Abduljabbar, K, Coelho-Lima, J, Grapa, A, Zhang, H, Cheung, A, Baena, J, Karasaki, T, Wilson, C, Sereno, M, Veeriah, S, Aitken, S, Hackshaw, A, Nicholson, A, Jamal-Hanjani, M, Le Quesne, J, Janes, S, Hacker, A, Sharp, A, Smith, S, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Lim, E, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Kidd, A, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Dick, C, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Tufail, M, Scotland, M, Boyles, R, Rathinam, S, Fennell, D, Marrone, D, Dulloo, S, Matharu, G, Shaw, J, Riley, J, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Papadatos-Pastos, D, Wilson, J, Ahmad, T, French, J, Gilbert, K, Naidu, B, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Paiva-Correia, A, Chaturvedi, A, Priest, L, Oliveira, P, Gomes, F, Brown, K, Carter, M, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Dive, C, Aerts, H, Schwarz, R, Kaufmann, T, Van Loo, P, Wilson, G, Rosenthal, R, Rowan, A, Bailey, C, Lee, C, Colliver, E, Enfield, K, Hill, M, Angelova, M, Pich, O, Leung, M, Frankell, A, Hiley, C, Zhai, H, Bakir, M, Birkbak, N, Lucas, O, Huebner, A, Puttick, C, Grigoriadis, K, Dietzen, M, Biswas, D, Athanasopoulou, F, Ward, S, Demeulemeester, J, Castignani, C, Cadieux, E, Kisistok, J, Sokac, M, Szallasi, Z, Diossy, M, Salgado, R, Stewart, A, Magness, A, Weeden, C, Levi, D, Gronroos, E, Noorani, I, Goldman, J, Escudero, M, Hobson, P, Vendramin, R, Boeing, S, Denner, T, Barbe, V, Lu, W, Hill, W, Naito, Y, Ramsden, Z, Kassiotis, G, Dwornik, A, Karamani, A, Chain, B, Pearce, D, Karagianni, D, Galvez-Cancino, F, Stavrou, G, Mastrokalos, G, Lowe, H, Matos, I, Reading, J, Hartley, J, Selvaraju, K, Chen, K, Ensell, L, Shah, M, Litovchenko, M, Chervova, O, Pawlik, P, Hynds, R, Gamble, S, Ung, S, Bola, S, Spanswick, V, Wu, Y, Al-Sawaf, O, Jones, T, Beck, S, Tanic, M, Marafioti, T, Borg, E, Falzon, M, Khiroya, R, Toncheva, A, Abbosh, C, Richard, C, Naceur-Lombardelli, C, Gimeno-Valiente, F, Thakkar, K, Sunderland, M, Sivakumar, M, Kanu, N, Prymas, P, Saghafinia, S, Vanloo, S, Lam, J, Liu, W, Bunkum, A, Hessey, S, Zaccaria, S, Martinez-Ruiz, C, Black, J, Thol, K, Bentham, R, Litchfield, K, Mcgranahan, N, Quezada, S, Forster, M, Lee, S, Herrero, J, Nye, E, Stone, R, Nicod, J, Rane, J, Peggs, K, Ng, K, Dijkstra, K, Huska, M, Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Gorman, P, Stephens, R, Wong, Y, Kaplar, Z, Bandula, S, Watkins, T, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Swanton, C, Yuan, Y, Moore, D, Pan X., AbdulJabbar K., Coelho-Lima J., Grapa A. -I., Zhang H., Cheung A. H. K., Baena J., Karasaki T., Wilson C. R., Sereno M., Veeriah S., Aitken S. J., Hackshaw A., Nicholson A. G., Jamal-Hanjani M., Le Quesne J., Janes S. M., Hacker A. -M., Sharp A., Smith S., Dhanda H. K., Chan K., Pilotti C., Leslie R., Chuter D., MacKenzie M., Chee S., Alzetani A., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Kidd A., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Dick C., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Tufail M., Scotland M., Boyles R., Rathinam S., Fennell D. A., Wilson C., Marrone D., Dulloo S., Matharu G., Shaw J. A., Riley J., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Papadatos-Pastos D., Wilson J., Ahmad T., French J., Gilbert K., Naidu B., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Paiva-Correia A., Chaturvedi A., Priest L., Oliveira P., Gomes F., Brown K., Carter M., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Dive C., Aerts H. J. W. L., Schwarz R. F., Kaufmann T. L., Van Loo P., Wilson G. A., Rosenthal R., Rowan A., Bailey C., Lee C., Colliver E., Enfield K. S. S., Hill M. S., Angelova M., Pich O., Leung M., Frankell A. M., Hiley C. T., Lim E. L., Zhai H., Bakir M. A., Birkbak N. J., Lucas O., Huebner A., Puttick C., Grigoriadis K., Dietzen M., Biswas D., Athanasopoulou F., Ward S., Demeulemeester J., Castignani C., Cadieux E. L., Kisistok J., Sokac M., Szallasi Z., Diossy M., Salgado R., Stewart A., Magness A., Weeden C. E., Levi D., Gronroos E., Noorani I., Goldman J., Escudero M., Hobson P., Vendramin R., Boeing S., Denner T., Barbe V., Lu W. -T., Hill W., Naito Y., Ramsden Z., Kassiotis G., Dwornik A., Karamani A., Chain B., Pearce D. R., Karagianni D., Galvez-Cancino F., Stavrou G., Mastrokalos G., Lowe H. L., Matos I. G., Reading J. L., Hartley J. A., Selvaraju K., Chen K., Ensell L., Shah M., Litovchenko M., Chervova O., Pawlik P., Hynds R. E., Gamble S., Ung S. K. A., Bola S. K., Spanswick V., Wu Y., Al-Sawaf O., Jones T. P., Beck S., Tanic M., Marafioti T., Borg E., Falzon M., Khiroya R., Toncheva A., Abbosh C., Richard C., Naceur-Lombardelli C., Gimeno-Valiente F., Thakkar K., Sunderland M. W., Sivakumar M., Kanu N., Prymas P., Saghafinia S., Vanloo S., Lam J. M., Liu W. K., Bunkum A., Hessey S., Zaccaria S., Martinez-Ruiz C., Black J. R. M., Thol K., Bentham R., Litchfield K., McGranahan N., Quezada S. A., Forster M. D., Lee S. M., Herrero J., Nye E., Stone R. K., Nicod J., Rane J. K., Peggs K. S., Ng K. W., Dijkstra K., Huska M. R., Hoogenboom E. M., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Gorman P., Stephens R. C. M., Wong Y. N. S., Kaplar Z., Bandula S., Watkins T. B. K., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Swanton C., Yuan Y., Moore D. A., Pan, X, Abduljabbar, K, Coelho-Lima, J, Grapa, A, Zhang, H, Cheung, A, Baena, J, Karasaki, T, Wilson, C, Sereno, M, Veeriah, S, Aitken, S, Hackshaw, A, Nicholson, A, Jamal-Hanjani, M, Le Quesne, J, Janes, S, Hacker, A, Sharp, A, Smith, S, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Lim, E, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Kidd, A, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Dick, C, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Tufail, M, Scotland, M, Boyles, R, Rathinam, S, Fennell, D, Marrone, D, Dulloo, S, Matharu, G, Shaw, J, Riley, J, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Papadatos-Pastos, D, Wilson, J, Ahmad, T, French, J, Gilbert, K, Naidu, B, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Paiva-Correia, A, Chaturvedi, A, Priest, L, Oliveira, P, Gomes, F, Brown, K, Carter, M, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Dive, C, Aerts, H, Schwarz, R, Kaufmann, T, Van Loo, P, Wilson, G, Rosenthal, R, Rowan, A, Bailey, C, Lee, C, Colliver, E, Enfield, K, Hill, M, Angelova, M, Pich, O, Leung, M, Frankell, A, Hiley, C, Zhai, H, Bakir, M, Birkbak, N, Lucas, O, Huebner, A, Puttick, C, Grigoriadis, K, Dietzen, M, Biswas, D, Athanasopoulou, F, Ward, S, Demeulemeester, J, Castignani, C, Cadieux, E, Kisistok, J, Sokac, M, Szallasi, Z, Diossy, M, Salgado, R, Stewart, A, Magness, A, Weeden, C, Levi, D, Gronroos, E, Noorani, I, Goldman, J, Escudero, M, Hobson, P, Vendramin, R, Boeing, S, Denner, T, Barbe, V, Lu, W, Hill, W, Naito, Y, Ramsden, Z, Kassiotis, G, Dwornik, A, Karamani, A, Chain, B, Pearce, D, Karagianni, D, Galvez-Cancino, F, Stavrou, G, Mastrokalos, G, Lowe, H, Matos, I, Reading, J, Hartley, J, Selvaraju, K, Chen, K, Ensell, L, Shah, M, Litovchenko, M, Chervova, O, Pawlik, P, Hynds, R, Gamble, S, Ung, S, Bola, S, Spanswick, V, Wu, Y, Al-Sawaf, O, Jones, T, Beck, S, Tanic, M, Marafioti, T, Borg, E, Falzon, M, Khiroya, R, Toncheva, A, Abbosh, C, Richard, C, Naceur-Lombardelli, C, Gimeno-Valiente, F, Thakkar, K, Sunderland, M, Sivakumar, M, Kanu, N, Prymas, P, Saghafinia, S, Vanloo, S, Lam, J, Liu, W, Bunkum, A, Hessey, S, Zaccaria, S, Martinez-Ruiz, C, Black, J, Thol, K, Bentham, R, Litchfield, K, Mcgranahan, N, Quezada, S, Forster, M, Lee, S, Herrero, J, Nye, E, Stone, R, Nicod, J, Rane, J, Peggs, K, Ng, K, Dijkstra, K, Huska, M, Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Gorman, P, Stephens, R, Wong, Y, Kaplar, Z, Bandula, S, Watkins, T, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Swanton, C, Yuan, Y, Moore, D, Pan X., AbdulJabbar K., Coelho-Lima J., Grapa A. -I., Zhang H., Cheung A. H. K., Baena J., Karasaki T., Wilson C. R., Sereno M., Veeriah S., Aitken S. J., Hackshaw A., Nicholson A. G., Jamal-Hanjani M., Le Quesne J., Janes S. M., Hacker A. -M., Sharp A., Smith S., Dhanda H. K., Chan K., Pilotti C., Leslie R., Chuter D., MacKenzie M., Chee S., Alzetani A., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Kidd A., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Dick C., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Tufail M., Scotland M., Boyles R., Rathinam S., Fennell D. A., Wilson C., Marrone D., Dulloo S., Matharu G., Shaw J. A., Riley J., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Papadatos-Pastos D., Wilson J., Ahmad T., French J., Gilbert K., Naidu B., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Paiva-Correia A., Chaturvedi A., Priest L., Oliveira P., Gomes F., Brown K., Carter M., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Dive C., Aerts H. J. W. L., Schwarz R. F., Kaufmann T. L., Van Loo P., Wilson G. A., Rosenthal R., Rowan A., Bailey C., Lee C., Colliver E., Enfield K. S. S., Hill M. S., Angelova M., Pich O., Leung M., Frankell A. M., Hiley C. T., Lim E. L., Zhai H., Bakir M. A., Birkbak N. J., Lucas O., Huebner A., Puttick C., Grigoriadis K., Dietzen M., Biswas D., Athanasopoulou F., Ward S., Demeulemeester J., Castignani C., Cadieux E. L., Kisistok J., Sokac M., Szallasi Z., Diossy M., Salgado R., Stewart A., Magness A., Weeden C. E., Levi D., Gronroos E., Noorani I., Goldman J., Escudero M., Hobson P., Vendramin R., Boeing S., Denner T., Barbe V., Lu W. -T., Hill W., Naito Y., Ramsden Z., Kassiotis G., Dwornik A., Karamani A., Chain B., Pearce D. R., Karagianni D., Galvez-Cancino F., Stavrou G., Mastrokalos G., Lowe H. L., Matos I. G., Reading J. L., Hartley J. A., Selvaraju K., Chen K., Ensell L., Shah M., Litovchenko M., Chervova O., Pawlik P., Hynds R. E., Gamble S., Ung S. K. A., Bola S. K., Spanswick V., Wu Y., Al-Sawaf O., Jones T. P., Beck S., Tanic M., Marafioti T., Borg E., Falzon M., Khiroya R., Toncheva A., Abbosh C., Richard C., Naceur-Lombardelli C., Gimeno-Valiente F., Thakkar K., Sunderland M. W., Sivakumar M., Kanu N., Prymas P., Saghafinia S., Vanloo S., Lam J. M., Liu W. K., Bunkum A., Hessey S., Zaccaria S., Martinez-Ruiz C., Black J. R. M., Thol K., Bentham R., Litchfield K., McGranahan N., Quezada S. A., Forster M. D., Lee S. M., Herrero J., Nye E., Stone R. K., Nicod J., Rane J. K., Peggs K. S., Ng K. W., Dijkstra K., Huska M. R., Hoogenboom E. M., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Gorman P., Stephens R. C. M., Wong Y. N. S., Kaplar Z., Bandula S., Watkins T. B. K., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Swanton C., Yuan Y., and Moore D. A.
- Abstract
The introduction of the International Association for the Study of Lung Cancer grading system has furthered interest in histopathological grading for risk stratification in lung adenocarcinoma. Complex morphology and high intratumoral heterogeneity present challenges to pathologists, prompting the development of artificial intelligence (AI) methods. Here we developed ANORAK (pyrAmid pooliNg crOss stReam Attention networK), encoding multiresolution inputs with an attention mechanism, to delineate growth patterns from hematoxylin and eosin-stained slides. In 1,372 lung adenocarcinomas across four independent cohorts, AI-based grading was prognostic of disease-free survival, and further assisted pathologists by consistently improving prognostication in stage I tumors. Tumors with discrepant patterns between AI and pathologists had notably higher intratumoral heterogeneity. Furthermore, ANORAK facilitates the morphological and spatial assessment of the acinar pattern, capturing acinus variations with pattern transition. Collectively, our AI method enabled the precision quantification and morphology investigation of growth patterns, reflecting intratumoral histological transitions in lung adenocarcinoma.
- Published
- 2024
14. CONIPHER: a computational framework for scalable phylogenetic reconstruction with error correction
- Author
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Grigoriadis, K, Huebner, A, Bunkum, A, Colliver, E, Frankell, A, Hill, M, Thol, K, Birkbak, N, Swanton, C, Zaccaria, S, Mcgranahan, N, Grigoriadis K., Huebner A., Bunkum A., Colliver E., Frankell A. M., Hill M. S., Thol K., Birkbak N. J., Swanton C., Zaccaria S., McGranahan N., Grigoriadis, K, Huebner, A, Bunkum, A, Colliver, E, Frankell, A, Hill, M, Thol, K, Birkbak, N, Swanton, C, Zaccaria, S, Mcgranahan, N, Grigoriadis K., Huebner A., Bunkum A., Colliver E., Frankell A. M., Hill M. S., Thol K., Birkbak N. J., Swanton C., Zaccaria S., and McGranahan N.
- Abstract
Intratumor heterogeneity provides the fuel for the evolution and selection of subclonal tumor cell populations. However, accurate inference of tumor subclonal architecture and reconstruction of tumor evolutionary histories from bulk DNA sequencing data remains challenging. Frequently, sequencing and alignment artifacts are not fully filtered out from cancer somatic mutations, and errors in the identification of copy number alterations or complex evolutionary events (e.g., mutation losses) affect the estimated cellular prevalence of mutations. Together, such errors propagate into the analysis of mutation clustering and phylogenetic reconstruction. In this Protocol, we present a new computational framework, CONIPHER (COrrecting Noise In PHylogenetic Evaluation and Reconstruction), that accurately infers subclonal structure and phylogenetic relationships from multisample tumor sequencing, accounting for both copy number alterations and mutation errors. CONIPHER has been used to reconstruct subclonal architecture and tumor phylogeny from multisample tumors with high-depth whole-exome sequencing from the TRACERx421 dataset, as well as matched primary-metastatic cases. CONIPHER outperforms similar methods on simulated datasets, and in particular scales to a large number of tumor samples and clones, while completing in under 1.5 h on average. CONIPHER enables automated phylogenetic analysis that can be effectively applied to large sequencing datasets generated with different technologies. CONIPHER can be run with a basic knowledge of bioinformatics and R and bash scripting languages.
- Published
- 2024
15. A compendium of genetic drivers for oesophageal adenocarcinoma defines prognostic and therapeutic biomarkers for use in the clinic
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Frankell, Alexander Mark and Fitzgerald, Rebecca C.
- Subjects
Cancer genomics ,Oesophgeal cancer ,Cancer evolution ,Biomarkers ,CDK4/6 inhibitors - Abstract
Background: Oesophageal adenocarcinoma (OAC) is a poor-prognosis cancer type with rapidly rising incidence. Understanding of the genetic events driving OAC development is limited, and there are few molecular biomarkers for prognostication or therapeutics. This study aimed to use a large cohort of genomically characterised OACs to determine the landscape of genetic driver events in OAC and their possible clinic uses. Methods: We have collated a cohort of 551 genomically characterized OACs (398 whole genome sequenced and 153 whole exome sequenced) with a sub-cohort matched to RNA sequencing data (116 cases). Strelka, Manta and ASCAT were used to call SNVs and indels, structural variants and copy number aberrations respectively. A suite of published tools was used to detect regions of the genome under positive selection for mutations in OAC including dNdScv, Mutsigcv, OncodriveFM and others. Copy number drivers were identified using GISTIC and correlations with matched expression data. Univariate and Multivariate cox regressions were used to identify prognostic biomarkers. Treatment of In vitro cultures of human OAC cell lines and organoids with a range of targeted therapeutics was used to calculate AUCs and GI50s for various drugs in OAC models. These sensitivities were matched to the genomic background in these cell lines, provided by whole genome sequencing. Results: We discovered 77 putative OAC driver genes and 21 putative noncoding driver elements for OAC. We identified a mean of 4.4 driver events per tumour, which were derived more commonly from mutations than copy number alterations and compared the prevalence of these mutations to the exome-wide mutational excess calculated using non-synonymous to synonymous mutation ratios (dN/dS). We observed mutual exclusivity or co-occurrence of events within and between several dysregulated OAC pathways, a result suggestive of strong functional relationships. Indicators of poor prognosis (SMAD4 and GATA4) were verified in independent cohorts with significant predictive value. Over 50% of OACs contained sensitizing events for CDK4 and CDK6 inhibitors, which were highly correlated with clinically relevant sensitivity in a panel of OAC cell lines and organoids. In a smaller panel of OACs we also saw evidence for specificity of BET inhibitor efficacy to MYC amplified OACs, however did not observe responses to EZH2 inhibitors, designed to target SWI/SNF mutated cancers, even upon induction of these mutations using CRISPR-Cas9. Discussion: We have complied the most comprehensive analysis to date of positively selected genomic elements in OAC, significantly improving upon previous analyses. We use this to identify prognostic and therapeutic biomarkers with considerable potential clinical value. Limitation to this study include a lack of RNA sequencing on all samples, making it difficult to assess selection for low-frequency copy number events. Future directions include functional investigation of many of the novel driver genes identified and prospective validation of clinical biomarkers in the Oelixir trial, including use of CDK4/6 inhibitors in OAC patients.
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- 2019
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16. Longitudinal tracking of 97 esophageal adenocarcinomas using liquid biopsy sampling
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Ococks, E., Frankell, A.M., Masque Soler, N., Grehan, N., Northrop, A., Coles, H., Redmond, A.M., Devonshire, G., Weaver, J.M.J., Hughes, C., Lehovsky, K., Blasko, A., Nutzinger, B., Fitzgerald, R.C., and Smyth, E.
- Published
- 2021
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17. Design and Implementation of a Performance Visualization Tool for the High-Level Parallel Programming Framework SkePU
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Frankell, Elin and Frankell, Elin
- Abstract
The rise of parallel programming languages, as a result of processors' flattening clock frequencies, has lead to further use of high-level parallel pattern-based programming framework such as SkePU. SkePU provides a sequential high-level interface connected to different back-ends, or a hybrid of several, which reduces the time required to learn several new programming languages. Although this high-level interface introduces a new problem, an abstraction layer from the user to what code is being executed. To make SkePU programs easier to analyze this thesis implements a performance visualization tool for SkePU. The conducted literature study found that there currently exists very few performance visualization tools that cater specifically towards skeleton programming languages. This thesis evaluates usability of the implemented tool by conducting a survey and a user study with participants whom are very familiar with SkePU. The choice of evaluation method is in itself critically evaluated, as is the design choices made, and results are presented with an accompanying discussion as to how those results were derived.
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- 2024
18. When can we be confident of surgical cure with ctDNA?
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Frankell, Alexander and Jamal-Hanjani, Mariam
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- 2022
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19. Abstract PR011: Comprehensive longitudinal tracking of lung cancer evolutionary clonal dynamics during therapy using circulating tumour DNA
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Frankell, Alexander M., primary, Abbosh, Christopher, additional, Grigoriadis, Kristiana, additional, Lim, Emilia, additional, Veeriah, Selvaraju, additional, Ward, Sophia, additional, Karasaki, Tak, additional, Black, James R. M., additional, Jamal-Hanjani, Mariam, additional, McGranahan, Nicholas, additional, and Swanton, Charles, additional
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- 2024
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20. Cancer Associated Bacteria in Primary and Metastatic Non-Small Cell Lung Cancer
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Thakkar, Krupa, primary, Richard, Corentin, additional, Fu, Hongchang, additional, Simpson, Benjamin S., additional, Cha, Hongui, additional, Augustine, Marcellus, additional, Coulton, Alexander, additional, Castro, Andrea, additional, Veerian, Selvaraju, additional, AbdulJabbar, Khalid, additional, Zhang, Hanyun, additional, Hardas, Alexandros, additional, Al-Sawaf, Othman, additional, Huebner, Arianna, additional, Al-Bakir, Maise, additional, Karasaki, Takahiro, additional, Pich, Oriol, additional, Bailey, Chris, additional, Seo, Yongwoo David, additional, Damania, Ashish, additional, Chelvanambi, Manoj, additional, Ajami, Nadim J., additional, Moore, David, additional, Sivakumar, Monika, additional, Hill, Mark, additional, Frankell, Alexander, additional, Ward, Sophie, additional, Naceur-Lombardelli, Cristina, additional, Salgado, Roberto, additional, Akarca, Ayse, additional, Marafioti, Teresa, additional, McGranahan, Nicholas, additional, Jamal-Hanjani, Mariam, additional, Wargo, Jennifer, additional, Santini, Joanne, additional, Swanton, Charles, additional, and Litchfield, Kevin, additional
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- 2024
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21. Body composition and lung cancer-associated cachexia in TRACERx
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Al-Sawaf, O, Weiss, J, Skrzypski, M, Lam, J, Karasaki, T, Zambrana, F, Kidd, A, Frankell, A, Watkins, T, Martinez-Ruiz, C, Puttick, C, Black, J, Huebner, A, Bakir, M, Sokac, M, Collins, S, Veeriah, S, Magno, N, Naceur-Lombardelli, C, Prymas, P, Toncheva, A, Ward, S, Jayanth, N, Salgado, R, Bridge, C, Christiani, D, Mak, R, Bay, C, Rosenthal, M, Sattar, N, Welsh, P, Liu, Y, Perrimon, N, Popuri, K, Beg, M, Mcgranahan, N, Hackshaw, A, Breen, D, O'Rahilly, S, Birkbak, N, Aerts, H, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Shaw, J, Riley, J, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Gilbert, K, Naidu, B, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Gomes, F, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Dive, C, Schwarz, R, Kaufmann, T, Wilson, G, Rosenthal, R, Van Loo, P, Szallasi, Z, Kisistok, J, Diossy, M, Demeulemeester, J, Bunkum, A, Stewart, A, Magness, A, Rowan, A, Karamani, A, Chain, B, Campbell, B, Castignani, C, Bailey, C, Abbosh, C, Weeden, C, Lee, C, Richard, C, Hiley, C, Moore, D, Pearce, D, Karagianni, D, Biswas, D, Levi, D, Hoxha, E, Cadieux, E, Lim, E, Colliver, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Athanasopoulou, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Zhai, H, Lowe, H, Matos, I, Goldman, J, Reading, J, Herrero, J, Rane, J, Nicod, J, Hartley, J, Peggs, K, Enfield, K, Selvaraju, K, Thol, K, Litchfield, K, Ng, K, Chen, K, Dijkstra, K, Grigoriadis, K, Thakkar, K, Ensell, L, Shah, M, Duran, M, Litovchenko, M, Sunderland, M, Hill, M, Dietzen, M, Leung, M, Escudero, M, Angelova, M, Tanic, M, Sivakumar, M, Kanu, N, Chervova, O, Lucas, O, Pich, O, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Hynds, R, Vendramin, R, Saghafinia, S, Lopez, S, Gamble, S, Ung, S, Quezada, S, Vanloo, S, Zaccaria, S, Hessey, S, Boeing, S, Beck, S, Bola, S, Denner, T, Marafioti, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Nicholson, A, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Dick, C, Le Quesne, J, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Jamal-Hanjani, M, Swanton, C, Al-Sawaf O., Weiss J., Skrzypski M., Lam J. M., Karasaki T., Zambrana F., Kidd A. C., Frankell A. M., Watkins T. B. K., Martinez-Ruiz C., Puttick C., Black J. R. M., Huebner A., Bakir M. A., Sokac M., Collins S., Veeriah S., Magno N., Naceur-Lombardelli C., Prymas P., Toncheva A., Ward S., Jayanth N., Salgado R., Bridge C. P., Christiani D. C., Mak R. H., Bay C., Rosenthal M., Sattar N., Welsh P., Liu Y., Perrimon N., Popuri K., Beg M. F., McGranahan N., Hackshaw A., Breen D. M., O'Rahilly S., Birkbak N. J., Aerts H. J. W. L., Aerts H. J., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Shaw J. A., Riley J., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Gilbert K., Naidu B., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Gomes F., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Dive C., Schwarz R. F., Kaufmann T. L., Wilson G. A., Rosenthal R., Van Loo P., Szallasi Z., Kisistok J., Diossy M., Demeulemeester J., Bunkum A., Stewart A., Magness A., Rowan A., Karamani A., Chain B., Campbell B. B., Castignani C., Bailey C., Abbosh C., Weeden C. E., Lee C., Richard C., Hiley C. T., Moore D. A., Pearce D. R., Karagianni D., Biswas D., Levi D., Hoxha E., Cadieux E. L., Lim E. L., Colliver E., Nye E., Gronroos E., Galvez-Cancino F., Athanasopoulou F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G., Zhai H., Lowe H. L., Matos I. G., Goldman J., Reading J. L., Herrero J., Rane J. K., Nicod J., Hartley J. A., Peggs K. S., Enfield K. S. S., Selvaraju K., Thol K., Litchfield K., Ng K. W., Chen K., Dijkstra K., Grigoriadis K., Thakkar K., Ensell L., Shah M., Duran M. V., Litovchenko M., Sunderland M. W., Hill M. S., Dietzen M., Leung M., Escudero M., Angelova M., Tanic M., Sivakumar M., Kanu N., Chervova O., Lucas O., Pich O., Hobson P., Pawlik P., Stone R. K., Bentham R., Hynds R. E., Vendramin R., Saghafinia S., Lopez S., Gamble S., Ung S. K. A., Quezada S. A., Vanloo S., Zaccaria S., Hessey S., Boeing S., Beck S., Bola S. K., Denner T., Marafioti T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Hoogenboom E. M., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Scarlett L., Richards J., Ingram P., Austin S., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Nicholson A. G., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Dick C., Le Quesne J., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Jamal-Hanjani M., Swanton C., Al-Sawaf, O, Weiss, J, Skrzypski, M, Lam, J, Karasaki, T, Zambrana, F, Kidd, A, Frankell, A, Watkins, T, Martinez-Ruiz, C, Puttick, C, Black, J, Huebner, A, Bakir, M, Sokac, M, Collins, S, Veeriah, S, Magno, N, Naceur-Lombardelli, C, Prymas, P, Toncheva, A, Ward, S, Jayanth, N, Salgado, R, Bridge, C, Christiani, D, Mak, R, Bay, C, Rosenthal, M, Sattar, N, Welsh, P, Liu, Y, Perrimon, N, Popuri, K, Beg, M, Mcgranahan, N, Hackshaw, A, Breen, D, O'Rahilly, S, Birkbak, N, Aerts, H, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Shaw, J, Riley, J, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Gilbert, K, Naidu, B, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Gomes, F, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Dive, C, Schwarz, R, Kaufmann, T, Wilson, G, Rosenthal, R, Van Loo, P, Szallasi, Z, Kisistok, J, Diossy, M, Demeulemeester, J, Bunkum, A, Stewart, A, Magness, A, Rowan, A, Karamani, A, Chain, B, Campbell, B, Castignani, C, Bailey, C, Abbosh, C, Weeden, C, Lee, C, Richard, C, Hiley, C, Moore, D, Pearce, D, Karagianni, D, Biswas, D, Levi, D, Hoxha, E, Cadieux, E, Lim, E, Colliver, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Athanasopoulou, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Zhai, H, Lowe, H, Matos, I, Goldman, J, Reading, J, Herrero, J, Rane, J, Nicod, J, Hartley, J, Peggs, K, Enfield, K, Selvaraju, K, Thol, K, Litchfield, K, Ng, K, Chen, K, Dijkstra, K, Grigoriadis, K, Thakkar, K, Ensell, L, Shah, M, Duran, M, Litovchenko, M, Sunderland, M, Hill, M, Dietzen, M, Leung, M, Escudero, M, Angelova, M, Tanic, M, Sivakumar, M, Kanu, N, Chervova, O, Lucas, O, Pich, O, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Hynds, R, Vendramin, R, Saghafinia, S, Lopez, S, Gamble, S, Ung, S, Quezada, S, Vanloo, S, Zaccaria, S, Hessey, S, Boeing, S, Beck, S, Bola, S, Denner, T, Marafioti, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Nicholson, A, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Dick, C, Le Quesne, J, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Jamal-Hanjani, M, Swanton, C, Al-Sawaf O., Weiss J., Skrzypski M., Lam J. M., Karasaki T., Zambrana F., Kidd A. C., Frankell A. M., Watkins T. B. K., Martinez-Ruiz C., Puttick C., Black J. R. M., Huebner A., Bakir M. A., Sokac M., Collins S., Veeriah S., Magno N., Naceur-Lombardelli C., Prymas P., Toncheva A., Ward S., Jayanth N., Salgado R., Bridge C. P., Christiani D. C., Mak R. H., Bay C., Rosenthal M., Sattar N., Welsh P., Liu Y., Perrimon N., Popuri K., Beg M. F., McGranahan N., Hackshaw A., Breen D. M., O'Rahilly S., Birkbak N. J., Aerts H. J. W. L., Aerts H. J., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Shaw J. A., Riley J., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Gilbert K., Naidu B., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Gomes F., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Dive C., Schwarz R. F., Kaufmann T. L., Wilson G. A., Rosenthal R., Van Loo P., Szallasi Z., Kisistok J., Diossy M., Demeulemeester J., Bunkum A., Stewart A., Magness A., Rowan A., Karamani A., Chain B., Campbell B. B., Castignani C., Bailey C., Abbosh C., Weeden C. E., Lee C., Richard C., Hiley C. T., Moore D. A., Pearce D. R., Karagianni D., Biswas D., Levi D., Hoxha E., Cadieux E. L., Lim E. L., Colliver E., Nye E., Gronroos E., Galvez-Cancino F., Athanasopoulou F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G., Zhai H., Lowe H. L., Matos I. G., Goldman J., Reading J. L., Herrero J., Rane J. K., Nicod J., Hartley J. A., Peggs K. S., Enfield K. S. S., Selvaraju K., Thol K., Litchfield K., Ng K. W., Chen K., Dijkstra K., Grigoriadis K., Thakkar K., Ensell L., Shah M., Duran M. V., Litovchenko M., Sunderland M. W., Hill M. S., Dietzen M., Leung M., Escudero M., Angelova M., Tanic M., Sivakumar M., Kanu N., Chervova O., Lucas O., Pich O., Hobson P., Pawlik P., Stone R. K., Bentham R., Hynds R. E., Vendramin R., Saghafinia S., Lopez S., Gamble S., Ung S. K. A., Quezada S. A., Vanloo S., Zaccaria S., Hessey S., Boeing S., Beck S., Bola S. K., Denner T., Marafioti T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Hoogenboom E. M., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Scarlett L., Richards J., Ingram P., Austin S., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Nicholson A. G., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Dick C., Le Quesne J., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Jamal-Hanjani M., and Swanton C.
- 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.
- Published
- 2023
22. Evolutionary characterization of lung adenocarcinoma morphology in TRACERx
- Author
-
Karasaki, T, Moore, D, Veeriah, S, Naceur-Lombardelli, C, Toncheva, A, Magno, N, Ward, S, Bakir, M, Watkins, T, Grigoriadis, K, Huebner, A, Hill, M, Frankell, A, Abbosh, C, Puttick, C, Zhai, H, Gimeno-Valiente, F, Saghafinia, S, Kanu, N, Dietzen, M, Pich, O, Lim, E, Martinez-Ruiz, C, Black, J, Biswas, D, Campbell, B, Lee, C, Colliver, E, Enfield, K, Hessey, S, Hiley, C, Zaccaria, S, Litchfield, K, Birkbak, N, Cadieux, E, Demeulemeester, J, Van Loo, P, Adusumilli, P, Tan, K, Cheema, W, Sanchez-Vega, F, Jones, D, Rekhtman, N, Travis, W, Hackshaw, A, Marafioti, T, Salgado, R, Le Quesne, J, Nicholson, A, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Shaw, J, Riley, J, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Gilbert, K, Naidu, B, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Gomes, F, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Dive, C, Aerts, H, Schwarz, R, Kaufmann, T, Wilson, G, Rosenthal, R, Szallasi, Z, Kisistok, J, Sokac, M, Diossy, M, Bunkum, A, Stewart, A, Magness, A, Rowan, A, Karamani, A, Chain, B, Castignani, C, Bailey, C, Weeden, C, Richard, C, Pearce, D, Karagianni, D, Levi, D, Hoxha, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Athanasopoulou, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Lowe, H, Matos, I, Goldman, J, Reading, J, Herrero, J, Rane, J, Nicod, J, Lam, J, Hartley, J, Peggs, K, Selvaraju, K, Thol, K, Ng, K, Chen, K, Dijkstra, K, Thakkar, K, Ensell, L, Shah, M, Duran, M, Litovchenko, M, Sunderland, M, Leung, M, Escudero, M, Angelova, M, Tanic, M, Sivakumar, M, Chervova, O, Lucas, O, Al-Sawaf, O, Prymas, P, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Hynds, R, Vendramin, R, Lopez, S, Gamble, S, Ung, S, Quezada, S, Vanloo, S, Boeing, S, Beck, S, Bola, S, Denner, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Dick, C, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Mcgranahan, N, Swanton, C, Jamal-Hanjani, M, Karasaki T., Moore D. A., Veeriah S., Naceur-Lombardelli C., Toncheva A., Magno N., Ward S., Bakir M. A., Watkins T. B. K., Grigoriadis K., Huebner A., Hill M. S., Frankell A. M., Abbosh C., Puttick C., Zhai H., Gimeno-Valiente F., Saghafinia S., Kanu N., Dietzen M., Pich O., Lim E. L., Martinez-Ruiz C., Black J. R. M., Biswas D., Campbell B. B., Lee C., Colliver E., Enfield K. S. S., Hessey S., Hiley C. T., Zaccaria S., Litchfield K., Birkbak N. J., Cadieux E. L., Demeulemeester J., Van Loo P., Adusumilli P. S., Tan K. S., Cheema W., Sanchez-Vega F., Jones D. R., Rekhtman N., Travis W. D., Hackshaw A., Marafioti T., Salgado R., Le Quesne J., Nicholson A. G., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Shaw J. A., Riley J., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Gilbert K., Naidu B., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Gomes F., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Dive C., Aerts H. J. W. L., Schwarz R. F., Kaufmann T. L., Wilson G. A., Rosenthal R., Szallasi Z., Kisistok J., Sokac M., Diossy M., Bunkum A., Stewart A., Magness A., Rowan A., Karamani A., Chain B., Castignani C., Bailey C., Weeden C. E., Richard C., Pearce D. R., Karagianni D., Levi D., Hoxha E., Nye E., Gronroos E., Galvez-Cancino F., Athanasopoulou F., Kassiotis G., Stavrou G., Mastrokalos G., Lowe H. L., Matos I. G., Goldman J., Reading J. L., Herrero J., Rane J. K., Nicod J., Lam J. M., Hartley J. A., Peggs K. S., Selvaraju K., Thol K., Ng K. W., Chen K., Dijkstra K., Thakkar K., Ensell L., Shah M., Duran M. V., Litovchenko M., Sunderland M. W., Leung M., Escudero M., Angelova M., Tanic M., Sivakumar M., Chervova O., Lucas O., Al-Sawaf O., Prymas P., Hobson P., Pawlik P., Stone R. K., Bentham R., Hynds R. E., Vendramin R., Lopez S., Gamble S., Ung S. K. A., Quezada S. A., Vanloo S., Boeing S., Beck S., Bola S. K., Denner T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Hoogenboom E. M., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Scarlett L., Richards J., Ingram P., Austin S., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Dick C., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., McGranahan N., Swanton C., Jamal-Hanjani M., Karasaki, T, Moore, D, Veeriah, S, Naceur-Lombardelli, C, Toncheva, A, Magno, N, Ward, S, Bakir, M, Watkins, T, Grigoriadis, K, Huebner, A, Hill, M, Frankell, A, Abbosh, C, Puttick, C, Zhai, H, Gimeno-Valiente, F, Saghafinia, S, Kanu, N, Dietzen, M, Pich, O, Lim, E, Martinez-Ruiz, C, Black, J, Biswas, D, Campbell, B, Lee, C, Colliver, E, Enfield, K, Hessey, S, Hiley, C, Zaccaria, S, Litchfield, K, Birkbak, N, Cadieux, E, Demeulemeester, J, Van Loo, P, Adusumilli, P, Tan, K, Cheema, W, Sanchez-Vega, F, Jones, D, Rekhtman, N, Travis, W, Hackshaw, A, Marafioti, T, Salgado, R, Le Quesne, J, Nicholson, A, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Shaw, J, Riley, J, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Gilbert, K, Naidu, B, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Gomes, F, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Dive, C, Aerts, H, Schwarz, R, Kaufmann, T, Wilson, G, Rosenthal, R, Szallasi, Z, Kisistok, J, Sokac, M, Diossy, M, Bunkum, A, Stewart, A, Magness, A, Rowan, A, Karamani, A, Chain, B, Castignani, C, Bailey, C, Weeden, C, Richard, C, Pearce, D, Karagianni, D, Levi, D, Hoxha, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Athanasopoulou, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Lowe, H, Matos, I, Goldman, J, Reading, J, Herrero, J, Rane, J, Nicod, J, Lam, J, Hartley, J, Peggs, K, Selvaraju, K, Thol, K, Ng, K, Chen, K, Dijkstra, K, Thakkar, K, Ensell, L, Shah, M, Duran, M, Litovchenko, M, Sunderland, M, Leung, M, Escudero, M, Angelova, M, Tanic, M, Sivakumar, M, Chervova, O, Lucas, O, Al-Sawaf, O, Prymas, P, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Hynds, R, Vendramin, R, Lopez, S, Gamble, S, Ung, S, Quezada, S, Vanloo, S, Boeing, S, Beck, S, Bola, S, Denner, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Dick, C, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Mcgranahan, N, Swanton, C, Jamal-Hanjani, M, Karasaki T., Moore D. A., Veeriah S., Naceur-Lombardelli C., Toncheva A., Magno N., Ward S., Bakir M. A., Watkins T. B. K., Grigoriadis K., Huebner A., Hill M. S., Frankell A. M., Abbosh C., Puttick C., Zhai H., Gimeno-Valiente F., Saghafinia S., Kanu N., Dietzen M., Pich O., Lim E. L., Martinez-Ruiz C., Black J. R. M., Biswas D., Campbell B. B., Lee C., Colliver E., Enfield K. S. S., Hessey S., Hiley C. T., Zaccaria S., Litchfield K., Birkbak N. J., Cadieux E. L., Demeulemeester J., Van Loo P., Adusumilli P. S., Tan K. S., Cheema W., Sanchez-Vega F., Jones D. R., Rekhtman N., Travis W. D., Hackshaw A., Marafioti T., Salgado R., Le Quesne J., Nicholson A. G., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Shaw J. A., Riley J., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Gilbert K., Naidu B., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Gomes F., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Dive C., Aerts H. J. W. L., Schwarz R. F., Kaufmann T. L., Wilson G. A., Rosenthal R., Szallasi Z., Kisistok J., Sokac M., Diossy M., Bunkum A., Stewart A., Magness A., Rowan A., Karamani A., Chain B., Castignani C., Bailey C., Weeden C. E., Richard C., Pearce D. R., Karagianni D., Levi D., Hoxha E., Nye E., Gronroos E., Galvez-Cancino F., Athanasopoulou F., Kassiotis G., Stavrou G., Mastrokalos G., Lowe H. L., Matos I. G., Goldman J., Reading J. L., Herrero J., Rane J. K., Nicod J., Lam J. M., Hartley J. A., Peggs K. S., Selvaraju K., Thol K., Ng K. W., Chen K., Dijkstra K., Thakkar K., Ensell L., Shah M., Duran M. V., Litovchenko M., Sunderland M. W., Leung M., Escudero M., Angelova M., Tanic M., Sivakumar M., Chervova O., Lucas O., Al-Sawaf O., Prymas P., Hobson P., Pawlik P., Stone R. K., Bentham R., Hynds R. E., Vendramin R., Lopez S., Gamble S., Ung S. K. A., Quezada S. A., Vanloo S., Boeing S., Beck S., Bola S. K., Denner T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Hoogenboom E. M., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Scarlett L., Richards J., Ingram P., Austin S., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Dick C., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., McGranahan N., Swanton C., and Jamal-Hanjani M.
- 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.
- Published
- 2023
23. Genomic–transcriptomic evolution in lung cancer and metastasis
- Author
-
Martinez-Ruiz, C, Black, J, Puttick, C, Hill, M, Demeulemeester, J, Larose Cadieux, E, Thol, K, Jones, T, Veeriah, S, Naceur-Lombardelli, C, Toncheva, A, Prymas, P, Rowan, A, Ward, S, Cubitt, L, Athanasopoulou, F, Pich, O, Karasaki, T, Moore, D, Salgado, R, Colliver, E, Castignani, C, Dietzen, M, Huebner, A, Al Bakir, M, Tanic, M, Watkins, T, Lim, E, Al-Rashed, A, Lang, D, Clements, J, Cook, D, Rosenthal, R, Wilson, G, Frankell, A, de Carne Trecesson, S, East, P, Kanu, N, Litchfield, K, Birkbak, N, Hackshaw, A, Beck, S, Van Loo, P, Jamal-Hanjani, M, Mcgranahan, N, Swanton, C, Bakir, M, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Shaw, J, Riley, J, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Gilbert, K, Naidu, B, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Gomes, F, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Dive, C, Aerts, H, Schwarz, R, Kaufmann, T, Szallasi, Z, Kisistok, J, Sokac, M, Diossy, M, Bunkum, A, Stewart, A, Magness, A, Karamani, A, Chain, B, Campbell, B, Bailey, C, Abbosh, C, Weeden, C, Lee, C, Richard, C, Hiley, C, Pearce, D, Karagianni, D, Biswas, D, Levi, D, Hoxha, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Zhai, H, Lowe, H, Matos, I, Goldman, J, Reading, J, Herrero, J, Rane, J, Nicod, J, Lam, J, Hartley, J, Peggs, K, Enfield, K, Selvaraju, K, Ng, K, Chen, K, Dijkstra, K, Grigoriadis, K, Thakkar, K, Ensell, L, Shah, M, Duran, M, Litovchenko, M, Sunderland, M, Leung, M, Escudero, M, Angelova, M, Sivakumar, M, Chervova, O, Lucas, O, Al-Sawaf, O, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Hynds, R, Vendramin, R, Saghafinia, S, Lopez, S, Gamble, S, Ung, S, Quezada, S, Vanloo, S, Zaccaria, S, Hessey, S, Boeing, S, Bola, S, Denner, T, Marafioti, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Nicholson, A, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Dick, C, Le Quesne, J, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Martinez-Ruiz C., Black J. R. M., Puttick C., Hill M. S., Demeulemeester J., Larose Cadieux E., Thol K., Jones T. P., Veeriah S., Naceur-Lombardelli C., Toncheva A., Prymas P., Rowan A., Ward S., Cubitt L., Athanasopoulou F., Pich O., Karasaki T., Moore D. A., Salgado R., Colliver E., Castignani C., Dietzen M., Huebner A., Al Bakir M., Tanic M., Watkins T. B. K., Lim E. L., Al-Rashed A. M., Lang D., Clements J., Cook D. E., Rosenthal R., Wilson G. A., Frankell A. M., de Carne Trecesson S., East P., Kanu N., Litchfield K., Birkbak N. J., Hackshaw A., Beck S., Van Loo P., Jamal-Hanjani M., McGranahan N., Swanton C., Bakir M. A., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Shaw J. A., Riley J., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Gilbert K., Naidu B., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Gomes F., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Dive C., Aerts H. J. W. L., Schwarz R. F., Kaufmann T. L., Szallasi Z., Kisistok J., Sokac M., Diossy M., Bunkum A., Stewart A., Magness A., Karamani A., Chain B., Campbell B. B., Bailey C., Abbosh C., Weeden C. E., Lee C., Richard C., Hiley C. T., Pearce D. R., Karagianni D., Biswas D., Levi D., Hoxha E., Nye E., Gronroos E., Galvez-Cancino F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G., Zhai H., Lowe H. L., Matos I. G., Goldman J., Reading J. L., Herrero J., Rane J. K., Nicod J., Lam J. M., Hartley J. A., Peggs K. S., Enfield K. S. S., Selvaraju K., Ng K. W., Chen K., Dijkstra K., Grigoriadis K., Thakkar K., Ensell L., Shah M., Duran M. V., Litovchenko M., Sunderland M. W., Leung M., Escudero M., Angelova M., Sivakumar M., Chervova O., Lucas O., Al-Sawaf O., Hobson P., Pawlik P., Stone R. K., Bentham R., Hynds R. E., Vendramin R., Saghafinia S., Lopez S., Gamble S., Ung S. K. A., Quezada S. A., Vanloo S., Zaccaria S., Hessey S., Boeing S., Bola S. K., Denner T., Marafioti T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Hoogenboom E. M., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C. M., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Scarlett L., Richards J., Ingram P., Austin S., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Nicholson A. G., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Dick C., Le Quesne J., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Martinez-Ruiz, C, Black, J, Puttick, C, Hill, M, Demeulemeester, J, Larose Cadieux, E, Thol, K, Jones, T, Veeriah, S, Naceur-Lombardelli, C, Toncheva, A, Prymas, P, Rowan, A, Ward, S, Cubitt, L, Athanasopoulou, F, Pich, O, Karasaki, T, Moore, D, Salgado, R, Colliver, E, Castignani, C, Dietzen, M, Huebner, A, Al Bakir, M, Tanic, M, Watkins, T, Lim, E, Al-Rashed, A, Lang, D, Clements, J, Cook, D, Rosenthal, R, Wilson, G, Frankell, A, de Carne Trecesson, S, East, P, Kanu, N, Litchfield, K, Birkbak, N, Hackshaw, A, Beck, S, Van Loo, P, Jamal-Hanjani, M, Mcgranahan, N, Swanton, C, Bakir, M, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Shaw, J, Riley, J, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Gilbert, K, Naidu, B, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Gomes, F, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Dive, C, Aerts, H, Schwarz, R, Kaufmann, T, Szallasi, Z, Kisistok, J, Sokac, M, Diossy, M, Bunkum, A, Stewart, A, Magness, A, Karamani, A, Chain, B, Campbell, B, Bailey, C, Abbosh, C, Weeden, C, Lee, C, Richard, C, Hiley, C, Pearce, D, Karagianni, D, Biswas, D, Levi, D, Hoxha, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Zhai, H, Lowe, H, Matos, I, Goldman, J, Reading, J, Herrero, J, Rane, J, Nicod, J, Lam, J, Hartley, J, Peggs, K, Enfield, K, Selvaraju, K, Ng, K, Chen, K, Dijkstra, K, Grigoriadis, K, Thakkar, K, Ensell, L, Shah, M, Duran, M, Litovchenko, M, Sunderland, M, Leung, M, Escudero, M, Angelova, M, Sivakumar, M, Chervova, O, Lucas, O, Al-Sawaf, O, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Hynds, R, Vendramin, R, Saghafinia, S, Lopez, S, Gamble, S, Ung, S, Quezada, S, Vanloo, S, Zaccaria, S, Hessey, S, Boeing, S, Bola, S, Denner, T, Marafioti, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Nicholson, A, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Dick, C, Le Quesne, J, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Martinez-Ruiz C., Black J. R. M., Puttick C., Hill M. S., Demeulemeester J., Larose Cadieux E., Thol K., Jones T. P., Veeriah S., Naceur-Lombardelli C., Toncheva A., Prymas P., Rowan A., Ward S., Cubitt L., Athanasopoulou F., Pich O., Karasaki T., Moore D. A., Salgado R., Colliver E., Castignani C., Dietzen M., Huebner A., Al Bakir M., Tanic M., Watkins T. B. K., Lim E. L., Al-Rashed A. M., Lang D., Clements J., Cook D. E., Rosenthal R., Wilson G. A., Frankell A. M., de Carne Trecesson S., East P., Kanu N., Litchfield K., Birkbak N. J., Hackshaw A., Beck S., Van Loo P., Jamal-Hanjani M., McGranahan N., Swanton C., Bakir M. A., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Shaw J. A., Riley J., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Gilbert K., Naidu B., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Gomes F., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Dive C., Aerts H. J. W. L., Schwarz R. F., Kaufmann T. L., Szallasi Z., Kisistok J., Sokac M., Diossy M., Bunkum A., Stewart A., Magness A., Karamani A., Chain B., Campbell B. B., Bailey C., Abbosh C., Weeden C. E., Lee C., Richard C., Hiley C. T., Pearce D. R., Karagianni D., Biswas D., Levi D., Hoxha E., Nye E., Gronroos E., Galvez-Cancino F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G., Zhai H., Lowe H. L., Matos I. G., Goldman J., Reading J. L., Herrero J., Rane J. K., Nicod J., Lam J. M., Hartley J. A., Peggs K. S., Enfield K. S. S., Selvaraju K., Ng K. W., Chen K., Dijkstra K., Grigoriadis K., Thakkar K., Ensell L., Shah M., Duran M. V., Litovchenko M., Sunderland M. W., Leung M., Escudero M., Angelova M., Sivakumar M., Chervova O., Lucas O., Al-Sawaf O., Hobson P., Pawlik P., Stone R. K., Bentham R., Hynds R. E., Vendramin R., Saghafinia S., Lopez S., Gamble S., Ung S. K. A., Quezada S. A., Vanloo S., Zaccaria S., Hessey S., Boeing S., Bola S. K., Denner T., Marafioti T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Hoogenboom E. M., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C. M., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Scarlett L., Richards J., Ingram P., Austin S., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Nicholson A. G., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Dick C., Le Quesne J., Kirk A., Asif M., Bilancia R., Kostoulas N., and Thomas M.
- Abstract
Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.
- Published
- 2023
24. Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA
- Author
-
Abbosh, C, Frankell, A, Harrison, T, Kisistok, J, Garnett, A, Johnson, L, Veeriah, S, Moreau, M, Chesh, A, Chaunzwa, T, Weiss, J, Schroeder, M, Ward, S, Grigoriadis, K, Shahpurwalla, A, Litchfield, K, Puttick, C, Biswas, D, Karasaki, T, Black, J, Martinez-Ruiz, C, Bakir, M, Pich, O, Watkins, T, Lim, E, Huebner, A, Moore, D, Godin-Heymann, N, L'Hernault, A, Bye, H, Odell, A, Roberts, P, Gomes, F, Patel, A, Manzano, E, Hiley, C, Carey, N, Riley, J, Cook, D, Hodgson, D, Stetson, D, Barrett, J, Kortlever, R, Evan, G, Hackshaw, A, Daber, R, Shaw, J, Aerts, H, Licon, A, Stahl, J, Jamal-Hanjani, M, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Gilbert, K, Naidu, B, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Dive, C, Schwarz, R, Kaufmann, T, Wilson, G, Rosenthal, R, Van Loo, P, Szallasi, Z, Sokac, M, Salgado, R, Diossy, M, Demeulemeester, J, Bunkum, A, Stewart, A, Magness, A, Rowan, A, Karamani, A, Toncheva, A, Chain, B, Campbell, B, Castignani, C, Bailey, C, Weeden, C, Lee, C, Richard, C, Naceur-Lombardelli, C, Pearce, D, Karagianni, D, Levi, D, Hoxha, E, Larose Cadieux, E, Colliver, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Athanasopoulou, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Zhai, H, Lowe, H, Matos, I, Goldman, J, Reading, J, Herrero, J, Rane, J, Nicod, J, Lam, J, Hartley, J, Peggs, K, Enfield, K, Selvaraju, K, Thol, K, Ng, K, Chen, K, Dijkstra, K, Thakkar, K, Ensell, L, Shah, M, Vasquez, M, Litovchenko, M, Werner Sunderland, M, Hill, M, Dietzen, M, Leung, M, Escudero, M, Angelova, M, Tanic, M, Sivakumar, M, Kanu, N, Chervova, O, Lucas, O, Al-Sawaf, O, Prymas, P, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Hynds, R, Vendramin, R, Saghafinia, S, Lopez, S, Gamble, S, Ung, S, Quezada, S, Vanloo, S, Zaccaria, S, Hessey, S, Boeing, S, Beck, S, Bola, S, Denner, T, Marafioti, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Martinoni Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Nicholson, A, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Dick, C, Le Quesne, J, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Birkbak, N, Mcgranahan, N, Swanton, C, Abbosh C., Frankell A. M., Harrison T., Kisistok J., Garnett A., Johnson L., Veeriah S., Moreau M., Chesh A., Chaunzwa T. L., Weiss J., Schroeder M. R., Ward S., Grigoriadis K., Shahpurwalla A., Litchfield K., Puttick C., Biswas D., Karasaki T., Black J. R. M., Martinez-Ruiz C., Bakir M. A., Pich O., Watkins T. B. K., Lim E. L., Huebner A., Moore D. A., Godin-Heymann N., L'Hernault A., Bye H., Odell A., Roberts P., Gomes F., Patel A. J., Manzano E., Hiley C. T., Carey N., Riley J., Cook D. E., Hodgson D., Stetson D., Barrett J. C., Kortlever R. M., Evan G. I., Hackshaw A., Daber R. D., Shaw J. A., Aerts H. J. W. L., Licon A., Stahl J., Jamal-Hanjani M., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Gilbert K., Naidu B., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Dive C., Schwarz R. F., Kaufmann T. L., Wilson G. A., Rosenthal R., Van Loo P., Szallasi Z., Sokac M., Salgado R., Diossy M., Demeulemeester J., Bunkum A., Stewart A., Magness A., Rowan A., Karamani A., Toncheva A., Chain B., Campbell B. B., Castignani C., Bailey C., Weeden C. E., Lee C., Richard C., Naceur-Lombardelli C., Pearce D. R., Karagianni D., Levi D., Hoxha E., Larose Cadieux E., Colliver E., Nye E., Gronroos E., Galvez-Cancino F., Athanasopoulou F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G., Zhai H., Lowe H. L., Matos I., Goldman J., Reading J. L., Herrero J., Rane J. K., Nicod J., Lam J. M., Hartley J. A., Peggs K. S., Enfield K. S. S., Selvaraju K., Thol K., Ng K. W., Chen K., Dijkstra K., Thakkar K., Ensell L., Shah M., Vasquez M., Litovchenko M., Werner Sunderland M., Hill M. S., Dietzen M., Leung M., Escudero M., Angelova M., Tanic M., Sivakumar M., Kanu N., Chervova O., Lucas O., Al-Sawaf O., Prymas P., Hobson P., Pawlik P., Stone R. K., Bentham R., Hynds R. E., Vendramin R., Saghafinia S., Lopez S., Gamble S., Ung S. K. A., Quezada S. A., Vanloo S., Zaccaria S., Hessey S., Boeing S., Beck S., Bola S. K., Denner T., Marafioti T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Martinoni Hoogenboom E., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Scarlett L., Richards J., Ingram P., Austin S., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Nicholson A. G., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Dick C., Le Quesne J., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Birkbak N. J., McGranahan N., Swanton C., Abbosh, C, Frankell, A, Harrison, T, Kisistok, J, Garnett, A, Johnson, L, Veeriah, S, Moreau, M, Chesh, A, Chaunzwa, T, Weiss, J, Schroeder, M, Ward, S, Grigoriadis, K, Shahpurwalla, A, Litchfield, K, Puttick, C, Biswas, D, Karasaki, T, Black, J, Martinez-Ruiz, C, Bakir, M, Pich, O, Watkins, T, Lim, E, Huebner, A, Moore, D, Godin-Heymann, N, L'Hernault, A, Bye, H, Odell, A, Roberts, P, Gomes, F, Patel, A, Manzano, E, Hiley, C, Carey, N, Riley, J, Cook, D, Hodgson, D, Stetson, D, Barrett, J, Kortlever, R, Evan, G, Hackshaw, A, Daber, R, Shaw, J, Aerts, H, Licon, A, Stahl, J, Jamal-Hanjani, M, Lester, J, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, D, Matharu, G, Primrose, L, Boleti, E, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Price, G, Kerr, K, Benafif, S, Gilbert, K, Naidu, B, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Middleton, G, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Dive, C, Schwarz, R, Kaufmann, T, Wilson, G, Rosenthal, R, Van Loo, P, Szallasi, Z, Sokac, M, Salgado, R, Diossy, M, Demeulemeester, J, Bunkum, A, Stewart, A, Magness, A, Rowan, A, Karamani, A, Toncheva, A, Chain, B, Campbell, B, Castignani, C, Bailey, C, Weeden, C, Lee, C, Richard, C, Naceur-Lombardelli, C, Pearce, D, Karagianni, D, Levi, D, Hoxha, E, Larose Cadieux, E, Colliver, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Athanasopoulou, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Zhai, H, Lowe, H, Matos, I, Goldman, J, Reading, J, Herrero, J, Rane, J, Nicod, J, Lam, J, Hartley, J, Peggs, K, Enfield, K, Selvaraju, K, Thol, K, Ng, K, Chen, K, Dijkstra, K, Thakkar, K, Ensell, L, Shah, M, Vasquez, M, Litovchenko, M, Werner Sunderland, M, Hill, M, Dietzen, M, Leung, M, Escudero, M, Angelova, M, Tanic, M, Sivakumar, M, Kanu, N, Chervova, O, Lucas, O, Al-Sawaf, O, Prymas, P, Hobson, P, Pawlik, P, Stone, R, Bentham, R, Hynds, R, Vendramin, R, Saghafinia, S, Lopez, S, Gamble, S, Ung, S, Quezada, S, Vanloo, S, Zaccaria, S, Hessey, S, Boeing, S, Beck, S, Bola, S, Denner, T, Marafioti, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Liu, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Forster, M, Lee, S, Borg, E, Falzon, M, Papadatos-Pastos, D, Wilson, J, Ahmad, T, Procter, A, Ahmed, A, Taylor, M, Nair, A, Lawrence, D, Patrini, D, Navani, N, Thakrar, R, Janes, S, Martinoni Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Cave, J, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Nicholson, A, Fernandes, N, Shah, P, Proli, C, Hewish, M, Danson, S, Shackcloth, M, Robinson, L, Russell, P, Blyth, K, Dick, C, Le Quesne, J, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Birkbak, N, Mcgranahan, N, Swanton, C, Abbosh C., Frankell A. M., Harrison T., Kisistok J., Garnett A., Johnson L., Veeriah S., Moreau M., Chesh A., Chaunzwa T. L., Weiss J., Schroeder M. R., Ward S., Grigoriadis K., Shahpurwalla A., Litchfield K., Puttick C., Biswas D., Karasaki T., Black J. R. M., Martinez-Ruiz C., Bakir M. A., Pich O., Watkins T. B. K., Lim E. L., Huebner A., Moore D. A., Godin-Heymann N., L'Hernault A., Bye H., Odell A., Roberts P., Gomes F., Patel A. J., Manzano E., Hiley C. T., Carey N., Riley J., Cook D. E., Hodgson D., Stetson D., Barrett J. C., Kortlever R. M., Evan G. I., Hackshaw A., Daber R. D., Shaw J. A., Aerts H. J. W. L., Licon A., Stahl J., Jamal-Hanjani M., Lester J. F., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Fennell D. A., Matharu G., Primrose L., Boleti E., Cheyne H., Khalil M., Richardson S., Cruickshank T., Price G., Kerr K. M., Benafif S., Gilbert K., Naidu B., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Middleton G., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Dive C., Schwarz R. F., Kaufmann T. L., Wilson G. A., Rosenthal R., Van Loo P., Szallasi Z., Sokac M., Salgado R., Diossy M., Demeulemeester J., Bunkum A., Stewart A., Magness A., Rowan A., Karamani A., Toncheva A., Chain B., Campbell B. B., Castignani C., Bailey C., Weeden C. E., Lee C., Richard C., Naceur-Lombardelli C., Pearce D. R., Karagianni D., Levi D., Hoxha E., Larose Cadieux E., Colliver E., Nye E., Gronroos E., Galvez-Cancino F., Athanasopoulou F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G., Zhai H., Lowe H. L., Matos I., Goldman J., Reading J. L., Herrero J., Rane J. K., Nicod J., Lam J. M., Hartley J. A., Peggs K. S., Enfield K. S. S., Selvaraju K., Thol K., Ng K. W., Chen K., Dijkstra K., Thakkar K., Ensell L., Shah M., Vasquez M., Litovchenko M., Werner Sunderland M., Hill M. S., Dietzen M., Leung M., Escudero M., Angelova M., Tanic M., Sivakumar M., Kanu N., Chervova O., Lucas O., Al-Sawaf O., Prymas P., Hobson P., Pawlik P., Stone R. K., Bentham R., Hynds R. E., Vendramin R., Saghafinia S., Lopez S., Gamble S., Ung S. K. A., Quezada S. A., Vanloo S., Zaccaria S., Hessey S., Boeing S., Beck S., Bola S. K., Denner T., Marafioti T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Liu W. K., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Forster M. D., Lee S. M., Borg E., Falzon M., Papadatos-Pastos D., Wilson J., Ahmad T., Procter A. J., Ahmed A., Taylor M. N., Nair A., Lawrence D., Patrini D., Navani N., Thakrar R. M., Janes S. M., Martinoni Hoogenboom E., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Cave J., Scarlett L., Richards J., Ingram P., Austin S., Lim E., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Nicholson A. G., Fernandes N., Shah P., Proli C., Hewish M., Danson S., Shackcloth M. J., Robinson L., Russell P., Blyth K. G., Dick C., Le Quesne J., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Birkbak N. J., McGranahan N., and Swanton C.
- Abstract
Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study2. A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy.
- Published
- 2023
25. Antibodies against endogenous retroviruses promote lung cancer immunotherapy
- Author
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Ng, K, Boumelha, J, Enfield, K, Almagro, J, Cha, H, Pich, O, Karasaki, T, Moore, D, Salgado, R, Sivakumar, M, Young, G, Molina-Arcas, M, de Carne Trecesson, S, Anastasiou, P, Fendler, A, Au, L, Shepherd, S, Martinez-Ruiz, C, Puttick, C, Black, J, Watkins, T, Kim, H, Shim, S, Faulkner, N, Attig, J, Veeriah, S, Magno, N, Ward, S, Frankell, A, Al Bakir, M, Lim, E, Hill, M, Wilson, G, Cook, D, Birkbak, N, Behrens, A, Yousaf, N, Popat, S, Hackshaw, A, Rowan, A, Huebner, A, Campbell, B, Bailey, C, Lee, C, Biswas, D, Colliver, E, Athanasopoulou, F, Zhai, H, Rane, J, Grigoriadis, K, Dietzen, M, Leung, M, Angelova, M, Lucas, O, Al-Sawaf, O, Rosenthal, R, Nicod, J, Bunkum, A, Toncheva, A, Abbosh, C, Richard, C, Naceur-Lombardelli, C, Gimeno-Valiente, F, Lam, J, Thol, K, Thakkar, K, Werner Sunderland, M, Forster, M, Kanu, N, Prymas, P, Bentham, R, Saghafinia, S, Quezada, S, Vanloo, S, Zaccaria, S, Lee, S, Hessey, S, Liu, W, Papadatos-Pastos, D, Wilson, J, Benafif, S, Ahmad, T, Borg, E, Falzon, M, Khiroya, R, Marafioti, T, Sharp, A, Pilotti, C, Dhanda, H, Chan, K, Gower, N, Leslie, R, Smith, S, Nicholson, A, Herrero, J, Castignani, C, Larose Cadieux, E, Demeulemeester, J, Van Loo, P, Peggs, K, Veiga, C, Royle, G, Collins-Fekete, C, Procter, A, Nair, A, Ahmed, A, Taylor, M, Navani, N, Thakrar, R, Lawrence, D, Patrini, D, Nye, E, Stone, R, Chuter, D, Mackenzie, M, Fraioli, F, Ashford, P, Janes, S, Tanic, M, Beck, S, Rice, A, Devaraj, A, Proli, C, Kaniu, D, Bhayani, H, Chavan, H, Raubenheimer, H, Ambrose, L, Malima, M, Fernandes, N, De Sousa, P, Shah, P, Booth, S, Buderi, S, Jordan, S, Begum, S, Boleti, E, Stewart, A, Magness, A, Weeden, C, Levi, D, Gronroos, E, Goldman, J, Escudero, M, Hobson, P, Vendramin, R, Boeing, S, Denner, T, Barbe, V, Lu, W, Hill, W, Naito, Y, Ramsden, Z, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Gilbert, K, Karamani, A, Chain, B, Pearce, D, Karagianni, D, Hoxha, E, Galvez-Cancino, F, Stavrou, G, Mastrokalos, G, Lowe, H, Matos, I, Reading, J, Hartley, J, Selvaraju, K, Chen, K, Ensell, L, Shah, M, Vasquez, M, Litovchenko, M, Chervova, O, Pawlik, P, Hynds, R, Lopez, S, Gamble, S, Ung, S, Bola, S, Mourikis, T, Spanswick, V, Wu, Y, Martinoni Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Stephens, R, Bandula, S, Wong, Y, Clark, T, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Naidu, B, Matharu, G, Shaw, J, Riley, J, Primrose, L, Le Quesne, J, Blyth, K, Kerr, A, Clipson, A, Chaturvedi, A, Dive, C, Rothwell, D, Kilgour, E, Tugwood, J, Priest, L, Oliveira, P, Crosbie, P, Price, G, Cave, J, Kerr, K, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Kirk, A, Thomas, M, Asif, M, Kostoulas, N, Bilancia, R, Middleton, G, Shackcloth, M, Leek, A, Hodgkinson, J, Totten, N, Dick, C, Robinson, L, Russell, P, Hewish, M, Danson, S, Lester, J, Gomes, F, Brown, K, Carter, M, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Alzetani, A, Richards, J, Scarlett, L, Ingram, P, Chee, S, Austin, S, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Fennell, D, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Aerts, H, Kaufmann, T, Schwarz, R, Kisistok, J, Sokac, M, Diossy, M, Szallasi, Z, Dijkstra, K, Yuan, Y, Byrne, F, Boos, L, Shum, B, Gerard, C, Schmitt, A, Messiou, C, Cunningham, D, Chau, I, Starling, N, Turner, N, Welsh, L, Jones, R, Droney, J, Banerjee, S, Tatham, K, Jhanji, S, Harrington, K, Okines, A, Reid, A, Young, K, Furness, A, Pickering, L, Nicholson, E, Kumar, S, Wilkinson, K, Swerdlow, A, Wilkinson, R, Hiley, C, Litchfield, K, Mcgranahan, N, Jamal-Hanjani, M, Larkin, J, Turajlic, S, Swanton, C, Downward, J, Kassiotis, G, Ng K. W., Boumelha J., Enfield K. S. S., Almagro J., Cha H., Pich O., Karasaki T., Moore D. A., Salgado R., Sivakumar M., Young G., Molina-Arcas M., de Carne Trecesson S., Anastasiou P., Fendler A., Au L., Shepherd S. T. C., Martinez-Ruiz C., Puttick C., Black J. R. M., Watkins T. B. K., Kim H., Shim S., Faulkner N., Attig J., Veeriah S., Magno N., Ward S., Frankell A. M., Al Bakir M., Lim E. L., Hill M. S., Wilson G. A., Cook D. E., Birkbak N. J., Behrens A., Yousaf N., Popat S., Hackshaw A., Rowan A., Huebner A., Campbell B. B., Bailey C., Lee C., Biswas D., Colliver E., Athanasopoulou F., Zhai H., Rane J. K., Grigoriadis K., Dietzen M., Leung M., Angelova M., Lucas O., Al-Sawaf O., Rosenthal R., Nicod J., Bunkum A., Toncheva A., Abbosh C., Richard C., Naceur-Lombardelli C., Gimeno-Valiente F., Lam J. M., Thol K., Thakkar K., Werner Sunderland M., Forster M. D., Kanu N., Prymas P., Bentham R., Saghafinia S., Quezada S. A., Vanloo S., Zaccaria S., Lee S. M., Hessey S., Liu W. K., Papadatos-Pastos D., Wilson J., Benafif S., Ahmad T., Borg E., Falzon M., Khiroya R., Marafioti T., Sharp A., Pilotti C., Dhanda H. K., Chan K., Gower N., Leslie R., Smith S., Nicholson A. G., Lim E., Herrero J., Castignani C., Larose Cadieux E., Demeulemeester J., Van Loo P., Peggs K. S., Veiga C., Royle G., Collins-Fekete C. -A., Procter A. J., Nair A., Ahmed A., Taylor M. N., Navani N., Thakrar R. M., Lawrence D., Patrini D., Nye E., Stone R. K., Chuter D., MacKenzie M., Fraioli F., Ashford P., Janes S. M., Tanic M., Beck S., Rice A., Devaraj A., Proli C., Kaniu D., Bhayani H., Chavan H., Raubenheimer H., Ambrose L., Malima M., Fernandes N., De Sousa P., Shah P., Booth S., Buderi S. I., Jordan S., Begum S., Boleti E., Stewart A., Magness A., Weeden C. E., Levi D., Gronroos E., Goldman J., Escudero M., Hobson P., Vendramin R., Boeing S., Denner T., Barbe V., Lu W. -T., Hill W., Naito Y., Ramsden Z., Grapa A., Zhang H., AbdulJabbar K., Pan X., Gilbert K., Karamani A., Chain B., Pearce D. R., Karagianni D., Hoxha E., Galvez-Cancino F., Stavrou G., Mastrokalos G., Lowe H. L., Matos I., Reading J. L., Hartley J. A., Selvaraju K., Chen K., Ensell L., Shah M., Vasquez M., Litovchenko M., Chervova O., Pawlik P., Hynds R. E., Lopez S., Gamble S., Ung S. K. A., Bola S. K., Mourikis T. P., Spanswick V., Wu Y., Martinoni Hoogenboom E., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Stephens R. C. M., Bandula S., Wong Y. N. S., Clark T., Cheyne H., Khalil M., Richardson S., Cruickshank T., Naidu B., Matharu G., Shaw J. A., Riley J., Primrose L., Le Quesne J., Blyth K. G., Kerr A., Clipson A., Chaturvedi A., Dive C., Rothwell D. G., Kilgour E., Tugwood J., Priest L., Oliveira P., Crosbie P., Price G., Cave J., Kerr K. M., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Kirk A., Thomas M., Asif M., Kostoulas N., Bilancia R., Middleton G., Shackcloth M. J., Leek A., Hodgkinson J. D., Totten N., Dick C., Robinson L., Russell P., Hewish M., Danson S., Lester J. F., Gomes F., Brown K., Carter M., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Alzetani A., Richards J., Scarlett L., Ingram P., Chee S., Austin S., Bajaj A., Nakas A., Sodha-Ramdeen A., Fennell D. A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Aerts H. J. W. L., Kaufmann T. L., Schwarz R. F., Kisistok J., Sokac M., Diossy M., Szallasi Z., Dijkstra K., Yuan Y., Byrne F., Boos L. A., Shum B., Gerard C. L., Schmitt A. M., Messiou C., Cunningham D., Chau I., Starling N., Turner N., Welsh L., Jones R. L., Droney J., Banerjee S., Tatham K. C., Jhanji S., Harrington K., Okines A., Reid A., Young K., Furness A. J. S., Pickering L., Nicholson E., Kumar S., Wilkinson K. A., Swerdlow A., Wilkinson R. J., Hiley C. T., Litchfield K., McGranahan N., Jamal-Hanjani M., Larkin J., Lee S. -H., Turajlic S., Swanton C., Downward J., Kassiotis G., Ng, K, Boumelha, J, Enfield, K, Almagro, J, Cha, H, Pich, O, Karasaki, T, Moore, D, Salgado, R, Sivakumar, M, Young, G, Molina-Arcas, M, de Carne Trecesson, S, Anastasiou, P, Fendler, A, Au, L, Shepherd, S, Martinez-Ruiz, C, Puttick, C, Black, J, Watkins, T, Kim, H, Shim, S, Faulkner, N, Attig, J, Veeriah, S, Magno, N, Ward, S, Frankell, A, Al Bakir, M, Lim, E, Hill, M, Wilson, G, Cook, D, Birkbak, N, Behrens, A, Yousaf, N, Popat, S, Hackshaw, A, Rowan, A, Huebner, A, Campbell, B, Bailey, C, Lee, C, Biswas, D, Colliver, E, Athanasopoulou, F, Zhai, H, Rane, J, Grigoriadis, K, Dietzen, M, Leung, M, Angelova, M, Lucas, O, Al-Sawaf, O, Rosenthal, R, Nicod, J, Bunkum, A, Toncheva, A, Abbosh, C, Richard, C, Naceur-Lombardelli, C, Gimeno-Valiente, F, Lam, J, Thol, K, Thakkar, K, Werner Sunderland, M, Forster, M, Kanu, N, Prymas, P, Bentham, R, Saghafinia, S, Quezada, S, Vanloo, S, Zaccaria, S, Lee, S, Hessey, S, Liu, W, Papadatos-Pastos, D, Wilson, J, Benafif, S, Ahmad, T, Borg, E, Falzon, M, Khiroya, R, Marafioti, T, Sharp, A, Pilotti, C, Dhanda, H, Chan, K, Gower, N, Leslie, R, Smith, S, Nicholson, A, Herrero, J, Castignani, C, Larose Cadieux, E, Demeulemeester, J, Van Loo, P, Peggs, K, Veiga, C, Royle, G, Collins-Fekete, C, Procter, A, Nair, A, Ahmed, A, Taylor, M, Navani, N, Thakrar, R, Lawrence, D, Patrini, D, Nye, E, Stone, R, Chuter, D, Mackenzie, M, Fraioli, F, Ashford, P, Janes, S, Tanic, M, Beck, S, Rice, A, Devaraj, A, Proli, C, Kaniu, D, Bhayani, H, Chavan, H, Raubenheimer, H, Ambrose, L, Malima, M, Fernandes, N, De Sousa, P, Shah, P, Booth, S, Buderi, S, Jordan, S, Begum, S, Boleti, E, Stewart, A, Magness, A, Weeden, C, Levi, D, Gronroos, E, Goldman, J, Escudero, M, Hobson, P, Vendramin, R, Boeing, S, Denner, T, Barbe, V, Lu, W, Hill, W, Naito, Y, Ramsden, Z, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Gilbert, K, Karamani, A, Chain, B, Pearce, D, Karagianni, D, Hoxha, E, Galvez-Cancino, F, Stavrou, G, Mastrokalos, G, Lowe, H, Matos, I, Reading, J, Hartley, J, Selvaraju, K, Chen, K, Ensell, L, Shah, M, Vasquez, M, Litovchenko, M, Chervova, O, Pawlik, P, Hynds, R, Lopez, S, Gamble, S, Ung, S, Bola, S, Mourikis, T, Spanswick, V, Wu, Y, Martinoni Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Stephens, R, Bandula, S, Wong, Y, Clark, T, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Naidu, B, Matharu, G, Shaw, J, Riley, J, Primrose, L, Le Quesne, J, Blyth, K, Kerr, A, Clipson, A, Chaturvedi, A, Dive, C, Rothwell, D, Kilgour, E, Tugwood, J, Priest, L, Oliveira, P, Crosbie, P, Price, G, Cave, J, Kerr, K, Lindsay, C, Blackhall, F, Krebs, M, Summers, Y, Kirk, A, Thomas, M, Asif, M, Kostoulas, N, Bilancia, R, Middleton, G, Shackcloth, M, Leek, A, Hodgkinson, J, Totten, N, Dick, C, Robinson, L, Russell, P, Hewish, M, Danson, S, Lester, J, Gomes, F, Brown, K, Carter, M, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Alzetani, A, Richards, J, Scarlett, L, Ingram, P, Chee, S, Austin, S, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Fennell, D, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Aerts, H, Kaufmann, T, Schwarz, R, Kisistok, J, Sokac, M, Diossy, M, Szallasi, Z, Dijkstra, K, Yuan, Y, Byrne, F, Boos, L, Shum, B, Gerard, C, Schmitt, A, Messiou, C, Cunningham, D, Chau, I, Starling, N, Turner, N, Welsh, L, Jones, R, Droney, J, Banerjee, S, Tatham, K, Jhanji, S, Harrington, K, Okines, A, Reid, A, Young, K, Furness, A, Pickering, L, Nicholson, E, Kumar, S, Wilkinson, K, Swerdlow, A, Wilkinson, R, Hiley, C, Litchfield, K, Mcgranahan, N, Jamal-Hanjani, M, Larkin, J, Turajlic, S, Swanton, C, Downward, J, Kassiotis, G, Ng K. W., Boumelha J., Enfield K. S. S., Almagro J., Cha H., Pich O., Karasaki T., Moore D. A., Salgado R., Sivakumar M., Young G., Molina-Arcas M., de Carne Trecesson S., Anastasiou P., Fendler A., Au L., Shepherd S. T. C., Martinez-Ruiz C., Puttick C., Black J. R. M., Watkins T. B. K., Kim H., Shim S., Faulkner N., Attig J., Veeriah S., Magno N., Ward S., Frankell A. M., Al Bakir M., Lim E. L., Hill M. S., Wilson G. A., Cook D. E., Birkbak N. J., Behrens A., Yousaf N., Popat S., Hackshaw A., Rowan A., Huebner A., Campbell B. B., Bailey C., Lee C., Biswas D., Colliver E., Athanasopoulou F., Zhai H., Rane J. K., Grigoriadis K., Dietzen M., Leung M., Angelova M., Lucas O., Al-Sawaf O., Rosenthal R., Nicod J., Bunkum A., Toncheva A., Abbosh C., Richard C., Naceur-Lombardelli C., Gimeno-Valiente F., Lam J. M., Thol K., Thakkar K., Werner Sunderland M., Forster M. D., Kanu N., Prymas P., Bentham R., Saghafinia S., Quezada S. A., Vanloo S., Zaccaria S., Lee S. M., Hessey S., Liu W. K., Papadatos-Pastos D., Wilson J., Benafif S., Ahmad T., Borg E., Falzon M., Khiroya R., Marafioti T., Sharp A., Pilotti C., Dhanda H. K., Chan K., Gower N., Leslie R., Smith S., Nicholson A. G., Lim E., Herrero J., Castignani C., Larose Cadieux E., Demeulemeester J., Van Loo P., Peggs K. S., Veiga C., Royle G., Collins-Fekete C. -A., Procter A. J., Nair A., Ahmed A., Taylor M. N., Navani N., Thakrar R. M., Lawrence D., Patrini D., Nye E., Stone R. K., Chuter D., MacKenzie M., Fraioli F., Ashford P., Janes S. M., Tanic M., Beck S., Rice A., Devaraj A., Proli C., Kaniu D., Bhayani H., Chavan H., Raubenheimer H., Ambrose L., Malima M., Fernandes N., De Sousa P., Shah P., Booth S., Buderi S. I., Jordan S., Begum S., Boleti E., Stewart A., Magness A., Weeden C. E., Levi D., Gronroos E., Goldman J., Escudero M., Hobson P., Vendramin R., Boeing S., Denner T., Barbe V., Lu W. -T., Hill W., Naito Y., Ramsden Z., Grapa A., Zhang H., AbdulJabbar K., Pan X., Gilbert K., Karamani A., Chain B., Pearce D. R., Karagianni D., Hoxha E., Galvez-Cancino F., Stavrou G., Mastrokalos G., Lowe H. L., Matos I., Reading J. L., Hartley J. A., Selvaraju K., Chen K., Ensell L., Shah M., Vasquez M., Litovchenko M., Chervova O., Pawlik P., Hynds R. E., Lopez S., Gamble S., Ung S. K. A., Bola S. K., Mourikis T. P., Spanswick V., Wu Y., Martinoni Hoogenboom E., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Stephens R. C. M., Bandula S., Wong Y. N. S., Clark T., Cheyne H., Khalil M., Richardson S., Cruickshank T., Naidu B., Matharu G., Shaw J. A., Riley J., Primrose L., Le Quesne J., Blyth K. G., Kerr A., Clipson A., Chaturvedi A., Dive C., Rothwell D. G., Kilgour E., Tugwood J., Priest L., Oliveira P., Crosbie P., Price G., Cave J., Kerr K. M., Lindsay C. R., Blackhall F. H., Krebs M. G., Summers Y., Kirk A., Thomas M., Asif M., Kostoulas N., Bilancia R., Middleton G., Shackcloth M. J., Leek A., Hodgkinson J. D., Totten N., Dick C., Robinson L., Russell P., Hewish M., Danson S., Lester J. F., Gomes F., Brown K., Carter M., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Alzetani A., Richards J., Scarlett L., Ingram P., Chee S., Austin S., Bajaj A., Nakas A., Sodha-Ramdeen A., Fennell D. A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Aerts H. J. W. L., Kaufmann T. L., Schwarz R. F., Kisistok J., Sokac M., Diossy M., Szallasi Z., Dijkstra K., Yuan Y., Byrne F., Boos L. A., Shum B., Gerard C. L., Schmitt A. M., Messiou C., Cunningham D., Chau I., Starling N., Turner N., Welsh L., Jones R. L., Droney J., Banerjee S., Tatham K. C., Jhanji S., Harrington K., Okines A., Reid A., Young K., Furness A. J. S., Pickering L., Nicholson E., Kumar S., Wilkinson K. A., Swerdlow A., Wilkinson R. J., Hiley C. T., Litchfield K., McGranahan N., Jamal-Hanjani M., Larkin J., Lee S. -H., Turajlic S., Swanton C., Downward J., and Kassiotis G.
- Abstract
B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.
- Published
- 2023
26. The evolution of lung cancer and impact of subclonal selection in TRACERx
- Author
-
Frankell, A, Dietzen, M, Al Bakir, M, Lim, E, Karasaki, T, Ward, S, Veeriah, S, Colliver, E, Huebner, A, Bunkum, A, Hill, M, Grigoriadis, K, Moore, D, Black, J, Liu, W, Thol, K, Pich, O, Watkins, T, Naceur-Lombardelli, C, Cook, D, Salgado, R, Wilson, G, Bailey, C, Angelova, M, Bentham, R, Martinez-Ruiz, C, Abbosh, C, Nicholson, A, Le Quesne, J, Biswas, D, Rosenthal, R, Puttick, C, Hessey, S, Lee, C, Prymas, P, Toncheva, A, Smith, J, Xing, W, Nicod, J, Price, G, Kerr, K, Naidu, B, Middleton, G, Blyth, K, Fennell, D, Forster, M, Lee, S, Falzon, M, Hewish, M, Shackcloth, M, Benafif, S, Russell, P, Boleti, E, Krebs, M, Lester, J, Papadatos-Pastos, D, Ahmad, T, Thakrar, R, Lawrence, D, Navani, N, Janes, S, Dive, C, Blackhall, F, Summers, Y, Cave, J, Marafioti, T, Herrero, J, Quezada, S, Peggs, K, Schwarz, R, Van Loo, P, Miedema, D, Birkbak, N, Hiley, C, Hackshaw, A, Zaccaria, S, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Matharu, G, Shaw, J, Riley, J, Primrose, L, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Gilbert, K, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Gomes, F, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Aerts, H, Kaufmann, T, Szallasi, Z, Kisistok, J, Sokac, M, Diossy, M, Demeulemeester, J, Stewart, A, Magness, A, Rowan, A, Karamani, A, Chain, B, Campbell, B, Castignani, C, Weeden, C, Richard, C, Pearce, D, Karagianni, D, Levi, D, Hoxha, E, Larose Cadieux, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Athanasopoulou, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Zhai, H, Lowe, H, Matos, I, Goldman, J, Reading, J, Rane, J, Lam, J, Hartley, J, Enfield, K, Selvaraju, K, Litchfield, K, Ng, K, Chen, K, Dijkstra, K, Thakkar, K, Ensell, L, Shah, M, Vasquez, M, Litovchenko, M, Werner Sunderland, M, Leung, M, Escudero, M, Tanic, M, Sivakumar, M, Kanu, N, Chervova, O, Lucas, O, Al-Sawaf, O, Hobson, P, Pawlik, P, Stone, R, Hynds, R, Vendramin, R, Saghafinia, S, Lopez, S, Gamble, S, Ung, S, Vanloo, S, Boeing, S, Beck, S, Bola, S, Denner, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Borg, E, Wilson, J, Procter, A, Ahmed, A, Taylor, M, Nair, A, Patrini, D, Martinoni Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Fernandes, N, Shah, P, Proli, C, Danson, S, Robinson, L, Dick, C, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Jamal-Hanjani, M, Mcgranahan, N, Swanton, C, Frankell A. M., Dietzen M., Al Bakir M., Lim E. L., Karasaki T., Ward S., Veeriah S., Colliver E., Huebner A., Bunkum A., Hill M. S., Grigoriadis K., Moore D. A., Black J. R. M., Liu W. K., Thol K., Pich O., Watkins T. B. K., Naceur-Lombardelli C., Cook D. E., Salgado R., Wilson G. A., Bailey C., Angelova M., Bentham R., Martinez-Ruiz C., Abbosh C., Nicholson A. G., Le Quesne J., Biswas D., Rosenthal R., Puttick C., Hessey S., Lee C., Prymas P., Toncheva A., Smith J., Xing W., Nicod J., Price G., Kerr K. M., Naidu B., Middleton G., Blyth K. G., Fennell D. A., Forster M. D., Lee S. M., Falzon M., Hewish M., Shackcloth M. J., Lim E., Benafif S., Russell P., Boleti E., Krebs M. G., Lester J. F., Papadatos-Pastos D., Ahmad T., Thakrar R. M., Lawrence D., Navani N., Janes S. M., Dive C., Blackhall F. H., Summers Y., Cave J., Marafioti T., Herrero J., Quezada S. A., Peggs K. S., Schwarz R. F., Van Loo P., Miedema D. M., Birkbak N. J., Hiley C. T., Hackshaw A., Zaccaria S., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Matharu G., Shaw J. A., Riley J., Primrose L., Cheyne H., Khalil M., Richardson S., Cruickshank T., Gilbert K., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Gomes F., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Aerts H. J. W. L., Kaufmann T. L., Szallasi Z., Kisistok J., Sokac M., Diossy M., Demeulemeester J., Stewart A., Magness A., Rowan A., Karamani A., Chain B., Campbell B. B., Castignani C., Weeden C. E., Richard C., Pearce D. R., Karagianni D., Levi D., Hoxha E., Larose Cadieux E., Nye E., Gronroos E., Galvez-Cancino F., Athanasopoulou F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G., Zhai H., Lowe H. L., Matos I., Goldman J., Reading J. L., Rane J. K., Lam J. M., Hartley J. A., Enfield K. S. S., Selvaraju K., Litchfield K., Ng K. W., Chen K., Dijkstra K., Thakkar K., Ensell L., Shah M., Vasquez M., Litovchenko M., Werner Sunderland M., Leung M., Escudero M., Tanic M., Sivakumar M., Kanu N., Chervova O., Lucas O., Al-Sawaf O., Hobson P., Pawlik P., Stone R. K., Hynds R. E., Vendramin R., Saghafinia S., Lopez S., Gamble S., Ung S. K. A., Vanloo S., Boeing S., Beck S., Bola S. K., Denner T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Borg E., Wilson J., Procter A. J., Ahmed A., Taylor M. N., Nair A., Patrini D., Martinoni Hoogenboom E., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Scarlett L., Richards J., Ingram P., Austin S., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Fernandes N., Shah P., Proli C., Danson S., Robinson L., Dick C., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Jamal-Hanjani M., McGranahan N., Swanton C., Frankell, A, Dietzen, M, Al Bakir, M, Lim, E, Karasaki, T, Ward, S, Veeriah, S, Colliver, E, Huebner, A, Bunkum, A, Hill, M, Grigoriadis, K, Moore, D, Black, J, Liu, W, Thol, K, Pich, O, Watkins, T, Naceur-Lombardelli, C, Cook, D, Salgado, R, Wilson, G, Bailey, C, Angelova, M, Bentham, R, Martinez-Ruiz, C, Abbosh, C, Nicholson, A, Le Quesne, J, Biswas, D, Rosenthal, R, Puttick, C, Hessey, S, Lee, C, Prymas, P, Toncheva, A, Smith, J, Xing, W, Nicod, J, Price, G, Kerr, K, Naidu, B, Middleton, G, Blyth, K, Fennell, D, Forster, M, Lee, S, Falzon, M, Hewish, M, Shackcloth, M, Benafif, S, Russell, P, Boleti, E, Krebs, M, Lester, J, Papadatos-Pastos, D, Ahmad, T, Thakrar, R, Lawrence, D, Navani, N, Janes, S, Dive, C, Blackhall, F, Summers, Y, Cave, J, Marafioti, T, Herrero, J, Quezada, S, Peggs, K, Schwarz, R, Van Loo, P, Miedema, D, Birkbak, N, Hiley, C, Hackshaw, A, Zaccaria, S, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Ang, K, Tufail, M, Chowdhry, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Matharu, G, Shaw, J, Riley, J, Primrose, L, Cheyne, H, Khalil, M, Richardson, S, Cruickshank, T, Gilbert, K, Patel, A, Osman, A, Lacson, C, Langman, G, Shackleford, H, Djearaman, M, Kadiri, S, Leek, A, Hodgkinson, J, Totten, N, Montero, A, Smith, E, Fontaine, E, Granato, F, Doran, H, Novasio, J, Rammohan, K, Joseph, L, Bishop, P, Shah, R, Moss, S, Joshi, V, Crosbie, P, Gomes, F, Brown, K, Carter, M, Chaturvedi, A, Priest, L, Oliveira, P, Lindsay, C, Clipson, A, Tugwood, J, Kerr, A, Rothwell, D, Kilgour, E, Aerts, H, Kaufmann, T, Szallasi, Z, Kisistok, J, Sokac, M, Diossy, M, Demeulemeester, J, Stewart, A, Magness, A, Rowan, A, Karamani, A, Chain, B, Campbell, B, Castignani, C, Weeden, C, Richard, C, Pearce, D, Karagianni, D, Levi, D, Hoxha, E, Larose Cadieux, E, Nye, E, Gronroos, E, Galvez-Cancino, F, Athanasopoulou, F, Gimeno-Valiente, F, Kassiotis, G, Stavrou, G, Mastrokalos, G, Zhai, H, Lowe, H, Matos, I, Goldman, J, Reading, J, Rane, J, Lam, J, Hartley, J, Enfield, K, Selvaraju, K, Litchfield, K, Ng, K, Chen, K, Dijkstra, K, Thakkar, K, Ensell, L, Shah, M, Vasquez, M, Litovchenko, M, Werner Sunderland, M, Leung, M, Escudero, M, Tanic, M, Sivakumar, M, Kanu, N, Chervova, O, Lucas, O, Al-Sawaf, O, Hobson, P, Pawlik, P, Stone, R, Hynds, R, Vendramin, R, Saghafinia, S, Lopez, S, Gamble, S, Ung, S, Vanloo, S, Boeing, S, Beck, S, Bola, S, Denner, T, Mourikis, T, Spanswick, V, Barbe, V, Lu, W, Hill, W, Wu, Y, Naito, Y, Ramsden, Z, Veiga, C, Royle, G, Collins-Fekete, C, Fraioli, F, Ashford, P, Clark, T, Borg, E, Wilson, J, Procter, A, Ahmed, A, Taylor, M, Nair, A, Patrini, D, Martinoni Hoogenboom, E, Monk, F, Holding, J, Choudhary, J, Bhakhri, K, Scarci, M, Hayward, M, Panagiotopoulos, N, Gorman, P, Khiroya, R, Stephens, R, Wong, Y, Bandula, S, Sharp, A, Smith, S, Gower, N, Dhanda, H, Chan, K, Pilotti, C, Leslie, R, Grapa, A, Zhang, H, Abduljabbar, K, Pan, X, Yuan, Y, Chuter, D, Mackenzie, M, Chee, S, Alzetani, A, Scarlett, L, Richards, J, Ingram, P, Austin, S, De Sousa, P, Jordan, S, Rice, A, Raubenheimer, H, Bhayani, H, Ambrose, L, Devaraj, A, Chavan, H, Begum, S, Buderi, S, Kaniu, D, Malima, M, Booth, S, Fernandes, N, Shah, P, Proli, C, Danson, S, Robinson, L, Dick, C, Kirk, A, Asif, M, Bilancia, R, Kostoulas, N, Thomas, M, Jamal-Hanjani, M, Mcgranahan, N, Swanton, C, Frankell A. M., Dietzen M., Al Bakir M., Lim E. L., Karasaki T., Ward S., Veeriah S., Colliver E., Huebner A., Bunkum A., Hill M. S., Grigoriadis K., Moore D. A., Black J. R. M., Liu W. K., Thol K., Pich O., Watkins T. B. K., Naceur-Lombardelli C., Cook D. E., Salgado R., Wilson G. A., Bailey C., Angelova M., Bentham R., Martinez-Ruiz C., Abbosh C., Nicholson A. G., Le Quesne J., Biswas D., Rosenthal R., Puttick C., Hessey S., Lee C., Prymas P., Toncheva A., Smith J., Xing W., Nicod J., Price G., Kerr K. M., Naidu B., Middleton G., Blyth K. G., Fennell D. A., Forster M. D., Lee S. M., Falzon M., Hewish M., Shackcloth M. J., Lim E., Benafif S., Russell P., Boleti E., Krebs M. G., Lester J. F., Papadatos-Pastos D., Ahmad T., Thakrar R. M., Lawrence D., Navani N., Janes S. M., Dive C., Blackhall F. H., Summers Y., Cave J., Marafioti T., Herrero J., Quezada S. A., Peggs K. S., Schwarz R. F., Van Loo P., Miedema D. M., Birkbak N. J., Hiley C. T., Hackshaw A., Zaccaria S., Bajaj A., Nakas A., Sodha-Ramdeen A., Ang K., Tufail M., Chowdhry M. F., Scotland M., Boyles R., Rathinam S., Wilson C., Marrone D., Dulloo S., Matharu G., Shaw J. A., Riley J., Primrose L., Cheyne H., Khalil M., Richardson S., Cruickshank T., Gilbert K., Patel A. J., Osman A., Lacson C., Langman G., Shackleford H., Djearaman M., Kadiri S., Leek A., Hodgkinson J. D., Totten N., Montero A., Smith E., Fontaine E., Granato F., Doran H., Novasio J., Rammohan K., Joseph L., Bishop P., Shah R., Moss S., Joshi V., Crosbie P., Gomes F., Brown K., Carter M., Chaturvedi A., Priest L., Oliveira P., Lindsay C. R., Clipson A., Tugwood J., Kerr A., Rothwell D. G., Kilgour E., Aerts H. J. W. L., Kaufmann T. L., Szallasi Z., Kisistok J., Sokac M., Diossy M., Demeulemeester J., Stewart A., Magness A., Rowan A., Karamani A., Chain B., Campbell B. B., Castignani C., Weeden C. E., Richard C., Pearce D. R., Karagianni D., Levi D., Hoxha E., Larose Cadieux E., Nye E., Gronroos E., Galvez-Cancino F., Athanasopoulou F., Gimeno-Valiente F., Kassiotis G., Stavrou G., Mastrokalos G., Zhai H., Lowe H. L., Matos I., Goldman J., Reading J. L., Rane J. K., Lam J. M., Hartley J. A., Enfield K. S. S., Selvaraju K., Litchfield K., Ng K. W., Chen K., Dijkstra K., Thakkar K., Ensell L., Shah M., Vasquez M., Litovchenko M., Werner Sunderland M., Leung M., Escudero M., Tanic M., Sivakumar M., Kanu N., Chervova O., Lucas O., Al-Sawaf O., Hobson P., Pawlik P., Stone R. K., Hynds R. E., Vendramin R., Saghafinia S., Lopez S., Gamble S., Ung S. K. A., Vanloo S., Boeing S., Beck S., Bola S. K., Denner T., Mourikis T. P., Spanswick V., Barbe V., Lu W. -T., Hill W., Wu Y., Naito Y., Ramsden Z., Veiga C., Royle G., Collins-Fekete C. -A., Fraioli F., Ashford P., Clark T., Borg E., Wilson J., Procter A. J., Ahmed A., Taylor M. N., Nair A., Patrini D., Martinoni Hoogenboom E., Monk F., Holding J. W., Choudhary J., Bhakhri K., Scarci M., Hayward M., Panagiotopoulos N., Gorman P., Khiroya R., Stephens R. C., Wong Y. N. S., Bandula S., Sharp A., Smith S., Gower N., Dhanda H. K., Chan K., Pilotti C., Leslie R., Grapa A., Zhang H., AbdulJabbar K., Pan X., Yuan Y., Chuter D., MacKenzie M., Chee S., Alzetani A., Scarlett L., Richards J., Ingram P., Austin S., De Sousa P., Jordan S., Rice A., Raubenheimer H., Bhayani H., Ambrose L., Devaraj A., Chavan H., Begum S., Buderi S. I., Kaniu D., Malima M., Booth S., Fernandes N., Shah P., Proli C., Danson S., Robinson L., Dick C., Kirk A., Asif M., Bilancia R., Kostoulas N., Thomas M., Jamal-Hanjani M., McGranahan N., and Swanton C.
- 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.
- Published
- 2023
27. Copy number architectures define treatment-mediated selection of lethal prostate cancer clones
- Author
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Hasan, A, Cremaschi, P, Wetterskog, D, Jayaram, A, Wong, S, Williams, S, Pasam, A, Trigos, A, Trujillo, B, Grist, E, Friedrich, S, Vainauskas, O, Parry, M, Ismail, M, Devlies, W, Wingate, A, Linch, M, Naceur-Lombardelli, C, Zaccaria, S, Hessey, S, Shiu, K, Bridgewater, J, Hochhauser, D, Forster, M, Lee, S, Ahmad, T, Papadatos-Pastos, D, Janes, S, Van Loo, P, Enfield, K, Mcgranahan, N, Huebner, A, Quezada, S, Beck, S, Parker, P, Enver, T, Hynds, R, Pearce, D, Falzon, M, Proctor, I, Sinclair, R, Lok, C, Rhodes, Z, Moore, D, Marafioti, T, Mitchison, M, Ellery, P, Sivakumar, M, Brandner, S, Rowan, A, Hiley, C, Veeriah, S, Shaw, H, Toncheva, A, Prymas, P, Watkins, T, Bailey, C, Martinez Ruiz, C, Litchfield, K, Al-Bakir, M, Kanu, N, Ward, S, Lim, E, Reading, J, Chain, B, Akay, M, Flanagan, A, Biswas, D, Pich, O, Dietzen, M, Puttick, C, Colliver, E, Magness, A, Angelova, M, Black, J, Lucas, O, Hill, W, Liu, W, Frankell, A, Magno, N, Athanasopoulou, F, Salgado, R, Lee, C, Grigoriadis, K, Al-Sawaf, O, Karasaki, T, Bunkum, A, Noorani, I, Benafif, S, Barbe, V, Bola, S, Leone, G, Alifrangis, C, Mcgovern, U, Thol, K, Gamble, S, Ung, S, Sahwangarrom, T, Marin, C, Pawlik, P, Lam, J, Richard, C, Vendramin, R, Dijkstra, K, Rane, J, Nicod, J, Dwornik, A, Bowles, K, Zaidi, R, Gishen, F, Stone, P, Stirling, C, Turajlic, S, Larkin, J, Pickering, L, Furness, A, Young, K, Drake, W, Edmonds, K, Hunter, N, Mangwende, M, Pearce, K, Grostate, L, Au, L, Spain, L, Shepherd, S, Yan, H, Shum, B, Tippu, Z, Hanley, B, Spencer, C, Emmerich, M, Gerard, C, Schmitt, A, Del Rosario, L, Carlyle, E, Lewis, C, Holt, L, Lucanas, A, O'Flaherty, M, Hazell, S, Mudhar, H, Messiou, C, Latifoltojar, A, Fendler, A, Byrne, F, Pallikonda, H, Lobon, I, Coulton, A, Cattin, A, Deng, D, Feng, H, Yousaf, N, Popat, S, Curtis, O, Milner-Watts, C, Stamp, G, Nye, E, Murra, A, Korteweg, J, Kelly, D, Terry, L, Biano, J, Peat, K, Kelly, K, Grieco, C, Le, M, D'Arienzo, P, Turay, E, Hill, P, Josephs, D, Irshad, S, Spicer, J, Mahadeva, U, Green, A, Stewart, R, Wright, N, Pulman, G, Mitu, R, Phillips-Boyd, S, Enting, D, Rudman, S, Ghosh, S, Karapanagiotou, E, Pintus, E, Tutt, A, Howlett, S, Brenton, J, Caldas, C, Fitzgerald, R, Jimenez-Linan, M, Provenzano, E, Cluroe, A, Paterson, A, Aitken, S, Allinson, K, Stewart, G, Mcdermott, U, Beddowes, E, Maughan, T, Ansorge, O, Campbell, P, Roxburgh, P, Fraser, S, Blyth, K, Le Quesne, J, Krebs, M, Blackhall, F, Summers, Y, Oliveira, P, Ortega-Franco, A, Dive, C, Gomes, F, Carter, M, Dransfield, J, Thomas, A, Fennell, D, Shaw, J, Wilson, C, Marrone, D, Naidu, B, Baijal, S, Tanchel, B, Langman, G, Robinson, A, Collard, M, Cockcroft, P, Ferris, C, Bancroft, H, Kerr, A, Middleton, G, Webb, J, Kadiri, S, Colloby, P, Olisemeke, B, Wilson, R, Shackleford, H, Osman, A, Tomlinson, I, Jogai, S, Holden, S, Fernandes, T, Mcneish, I, Hampton, B, Mckenzie, M, Hackshaw, A, Sharp, A, Chan, K, Farrelly, L, Bridger, H, Leslie, R, Tookman, A, Swanton, C, Jamal-Hanjani, M, Lise, S, Sandhu, S, Attard, G, Hasan A. M. M., Cremaschi P., Wetterskog D., Jayaram A., Wong S. Q., Williams S., Pasam A., Trigos A., Trujillo B., Grist E., Friedrich S., Vainauskas O., Parry M., Ismail M., Devlies W., Wingate A., Linch M., Naceur-Lombardelli C., Zaccaria S., Hessey S., Shiu K. -K., Bridgewater J., Hochhauser D., Forster M., Lee S. -M., Ahmad T., Papadatos-Pastos D., Janes S., Van Loo P., Enfield K., McGranahan N., Huebner A., Quezada S., Beck S., Parker P., Enver T., Hynds R. E., Pearce D. R., Falzon M., Proctor I., Sinclair R., Lok C. -W., Rhodes Z., Moore D., Marafioti T., Mitchison M., Ellery P., Sivakumar M., Brandner S., Rowan A., Hiley C., Veeriah S., Shaw H., Toncheva A., Prymas P., Watkins T. B. K., Bailey C., Martinez Ruiz C., Litchfield K., Al-Bakir M., Kanu N., Ward S., Lim E., Reading J., Chain B., Watkins T., Akay M., Flanagan A., Biswas D., Pich O., Dietzen M., Puttick C., Colliver E., Magness A., Angelova M., Black J., Lucas O., Hill W., Liu W. -K., Frankell A., Magno N., Athanasopoulou F., Salgado R., Lee C., Grigoriadis K., Al-Sawaf O., Karasaki T., Bunkum A., Noorani I., Benafif S., Barbe V., Bola S. K., Leone G., Alifrangis C., McGovern U., Thol K., Gamble S., Ung S. K., Sahwangarrom T., Marin C. P., Wong S., Pawlik P., Lam J. M., Richard C., Vendramin R., Dijkstra K., Rane J., Nicod J., Dwornik A., Bowles K., Zaidi R., Gishen F., Stone P., Stirling C., Turajlic S., Larkin J., Pickering L., Furness A., Young K., Drake W., Edmonds K., Hunter N., Mangwende M., Pearce K., Grostate L., Au L., Spain L., Shepherd S., Yan H., Shum B., Tippu Z., Hanley B., Spencer C., Emmerich M., Gerard C., Schmitt A. M., Del Rosario L., Carlyle E., Lewis C., Holt L., Lucanas A., O'Flaherty M., Hazell S., Mudhar H., Messiou C., Latifoltojar A., Fendler A., Byrne F., Pallikonda H., Lobon I., Coulton A., Cattin A. -L., Deng D., Feng H., Yousaf N., Popat S., Curtis O., Milner-Watts C., Stamp G., Nye E., Murra A., Korteweg J., Kelly D., Terry L., Biano J., Peat K., Kelly K., Grieco C., Le M. L., D'Arienzo P. D., Turay E., Hill P., Josephs D., Irshad S., Spicer J., Mahadeva U., Green A., Stewart R., Wright N., Pulman G., Mitu R., Phillips-Boyd S., Enting D., Rudman S., Ghosh S., Karapanagiotou E., Pintus E., Tutt A., Howlett S., Brenton J., Caldas C., Fitzgerald R., Jimenez-Linan M., Provenzano E., Cluroe A., Paterson A., Aitken S., Allinson K., Stewart G., McDermott U., Beddowes E., Maughan T., Ansorge O., Campbell P., Roxburgh P., Fraser S., Blyth K., Le Quesne J., Krebs M., Blackhall F., Summers Y., Oliveira P., Ortega-Franco A., Dive C., Gomes F., Carter M., Dransfield J., Thomas A., Fennell D., Shaw J., Wilson C., Marrone D., Naidu B., Baijal S., Tanchel B., Langman G., Robinson A., Collard M., Cockcroft P., Ferris C., Bancroft H., Kerr A., Middleton G., Webb J., Kadiri S., Colloby P., Olisemeke B., Wilson R., Shackleford H., Osman A., Tomlinson I., Jogai S., Holden S., Fernandes T., McNeish I., Hampton B., McKenzie M., Hackshaw A., Sharp A., Chan K., Farrelly L., Bridger H., Leslie R., Tookman A., Swanton C., Jamal-Hanjani M., Lise S., Sandhu S., Attard G., Hasan, A, Cremaschi, P, Wetterskog, D, Jayaram, A, Wong, S, Williams, S, Pasam, A, Trigos, A, Trujillo, B, Grist, E, Friedrich, S, Vainauskas, O, Parry, M, Ismail, M, Devlies, W, Wingate, A, Linch, M, Naceur-Lombardelli, C, Zaccaria, S, Hessey, S, Shiu, K, Bridgewater, J, Hochhauser, D, Forster, M, Lee, S, Ahmad, T, Papadatos-Pastos, D, Janes, S, Van Loo, P, Enfield, K, Mcgranahan, N, Huebner, A, Quezada, S, Beck, S, Parker, P, Enver, T, Hynds, R, Pearce, D, Falzon, M, Proctor, I, Sinclair, R, Lok, C, Rhodes, Z, Moore, D, Marafioti, T, Mitchison, M, Ellery, P, Sivakumar, M, Brandner, S, Rowan, A, Hiley, C, Veeriah, S, Shaw, H, Toncheva, A, Prymas, P, Watkins, T, Bailey, C, Martinez Ruiz, C, Litchfield, K, Al-Bakir, M, Kanu, N, Ward, S, Lim, E, Reading, J, Chain, B, Akay, M, Flanagan, A, Biswas, D, Pich, O, Dietzen, M, Puttick, C, Colliver, E, Magness, A, Angelova, M, Black, J, Lucas, O, Hill, W, Liu, W, Frankell, A, Magno, N, Athanasopoulou, F, Salgado, R, Lee, C, Grigoriadis, K, Al-Sawaf, O, Karasaki, T, Bunkum, A, Noorani, I, Benafif, S, Barbe, V, Bola, S, Leone, G, Alifrangis, C, Mcgovern, U, Thol, K, Gamble, S, Ung, S, Sahwangarrom, T, Marin, C, Pawlik, P, Lam, J, Richard, C, Vendramin, R, Dijkstra, K, Rane, J, Nicod, J, Dwornik, A, Bowles, K, Zaidi, R, Gishen, F, Stone, P, Stirling, C, Turajlic, S, Larkin, J, Pickering, L, Furness, A, Young, K, Drake, W, Edmonds, K, Hunter, N, Mangwende, M, Pearce, K, Grostate, L, Au, L, Spain, L, Shepherd, S, Yan, H, Shum, B, Tippu, Z, Hanley, B, Spencer, C, Emmerich, M, Gerard, C, Schmitt, A, Del Rosario, L, Carlyle, E, Lewis, C, Holt, L, Lucanas, A, O'Flaherty, M, Hazell, S, Mudhar, H, Messiou, C, Latifoltojar, A, Fendler, A, Byrne, F, Pallikonda, H, Lobon, I, Coulton, A, Cattin, A, Deng, D, Feng, H, Yousaf, N, Popat, S, Curtis, O, Milner-Watts, C, Stamp, G, Nye, E, Murra, A, Korteweg, J, Kelly, D, Terry, L, Biano, J, Peat, K, Kelly, K, Grieco, C, Le, M, D'Arienzo, P, Turay, E, Hill, P, Josephs, D, Irshad, S, Spicer, J, Mahadeva, U, Green, A, Stewart, R, Wright, N, Pulman, G, Mitu, R, Phillips-Boyd, S, Enting, D, Rudman, S, Ghosh, S, Karapanagiotou, E, Pintus, E, Tutt, A, Howlett, S, Brenton, J, Caldas, C, Fitzgerald, R, Jimenez-Linan, M, Provenzano, E, Cluroe, A, Paterson, A, Aitken, S, Allinson, K, Stewart, G, Mcdermott, U, Beddowes, E, Maughan, T, Ansorge, O, Campbell, P, Roxburgh, P, Fraser, S, Blyth, K, Le Quesne, J, Krebs, M, Blackhall, F, Summers, Y, Oliveira, P, Ortega-Franco, A, Dive, C, Gomes, F, Carter, M, Dransfield, J, Thomas, A, Fennell, D, Shaw, J, Wilson, C, Marrone, D, Naidu, B, Baijal, S, Tanchel, B, Langman, G, Robinson, A, Collard, M, Cockcroft, P, Ferris, C, Bancroft, H, Kerr, A, Middleton, G, Webb, J, Kadiri, S, Colloby, P, Olisemeke, B, Wilson, R, Shackleford, H, Osman, A, Tomlinson, I, Jogai, S, Holden, S, Fernandes, T, Mcneish, I, Hampton, B, Mckenzie, M, Hackshaw, A, Sharp, A, Chan, K, Farrelly, L, Bridger, H, Leslie, R, Tookman, A, Swanton, C, Jamal-Hanjani, M, Lise, S, Sandhu, S, Attard, G, Hasan A. M. M., Cremaschi P., Wetterskog D., Jayaram A., Wong S. Q., Williams S., Pasam A., Trigos A., Trujillo B., Grist E., Friedrich S., Vainauskas O., Parry M., Ismail M., Devlies W., Wingate A., Linch M., Naceur-Lombardelli C., Zaccaria S., Hessey S., Shiu K. -K., Bridgewater J., Hochhauser D., Forster M., Lee S. -M., Ahmad T., Papadatos-Pastos D., Janes S., Van Loo P., Enfield K., McGranahan N., Huebner A., Quezada S., Beck S., Parker P., Enver T., Hynds R. E., Pearce D. R., Falzon M., Proctor I., Sinclair R., Lok C. -W., Rhodes Z., Moore D., Marafioti T., Mitchison M., Ellery P., Sivakumar M., Brandner S., Rowan A., Hiley C., Veeriah S., Shaw H., Toncheva A., Prymas P., Watkins T. B. K., Bailey C., Martinez Ruiz C., Litchfield K., Al-Bakir M., Kanu N., Ward S., Lim E., Reading J., Chain B., Watkins T., Akay M., Flanagan A., Biswas D., Pich O., Dietzen M., Puttick C., Colliver E., Magness A., Angelova M., Black J., Lucas O., Hill W., Liu W. -K., Frankell A., Magno N., Athanasopoulou F., Salgado R., Lee C., Grigoriadis K., Al-Sawaf O., Karasaki T., Bunkum A., Noorani I., Benafif S., Barbe V., Bola S. K., Leone G., Alifrangis C., McGovern U., Thol K., Gamble S., Ung S. K., Sahwangarrom T., Marin C. P., Wong S., Pawlik P., Lam J. M., Richard C., Vendramin R., Dijkstra K., Rane J., Nicod J., Dwornik A., Bowles K., Zaidi R., Gishen F., Stone P., Stirling C., Turajlic S., Larkin J., Pickering L., Furness A., Young K., Drake W., Edmonds K., Hunter N., Mangwende M., Pearce K., Grostate L., Au L., Spain L., Shepherd S., Yan H., Shum B., Tippu Z., Hanley B., Spencer C., Emmerich M., Gerard C., Schmitt A. M., Del Rosario L., Carlyle E., Lewis C., Holt L., Lucanas A., O'Flaherty M., Hazell S., Mudhar H., Messiou C., Latifoltojar A., Fendler A., Byrne F., Pallikonda H., Lobon I., Coulton A., Cattin A. -L., Deng D., Feng H., Yousaf N., Popat S., Curtis O., Milner-Watts C., Stamp G., Nye E., Murra A., Korteweg J., Kelly D., Terry L., Biano J., Peat K., Kelly K., Grieco C., Le M. L., D'Arienzo P. D., Turay E., Hill P., Josephs D., Irshad S., Spicer J., Mahadeva U., Green A., Stewart R., Wright N., Pulman G., Mitu R., Phillips-Boyd S., Enting D., Rudman S., Ghosh S., Karapanagiotou E., Pintus E., Tutt A., Howlett S., Brenton J., Caldas C., Fitzgerald R., Jimenez-Linan M., Provenzano E., Cluroe A., Paterson A., Aitken S., Allinson K., Stewart G., McDermott U., Beddowes E., Maughan T., Ansorge O., Campbell P., Roxburgh P., Fraser S., Blyth K., Le Quesne J., Krebs M., Blackhall F., Summers Y., Oliveira P., Ortega-Franco A., Dive C., Gomes F., Carter M., Dransfield J., Thomas A., Fennell D., Shaw J., Wilson C., Marrone D., Naidu B., Baijal S., Tanchel B., Langman G., Robinson A., Collard M., Cockcroft P., Ferris C., Bancroft H., Kerr A., Middleton G., Webb J., Kadiri S., Colloby P., Olisemeke B., Wilson R., Shackleford H., Osman A., Tomlinson I., Jogai S., Holden S., Fernandes T., McNeish I., Hampton B., McKenzie M., Hackshaw A., Sharp A., Chan K., Farrelly L., Bridger H., Leslie R., Tookman A., Swanton C., Jamal-Hanjani M., Lise S., Sandhu S., and Attard G.
- Abstract
Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient evolutionary relationships of metastases that evade treatment, we perform genome-wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 167 metastatic regions from 11 organs harvested post-mortem from 10 men who died from prostate cancer. We identify diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR-neutral clones. Using the genomic boundaries of pan-autosome copy number changes, we confirm a common clone of origin across metastases and diagnostic biopsies, and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations. These autosome-defined clusters are characterized by cluster-specific AR gene architectures, and in two index cases are topologically more congruent than by chance (p-values 3.07 × 10−8 and 6.4 × 10−4). Integration with anatomical sites suggests patterns of spread and points of genomic divergence. Here, we show that copy number boundaries identify treatment-selected clones with putatively distinct lethal trajectories.
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- 2023
28. CONIPHER: a computational framework for scalable phylogenetic reconstruction with error correction
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Grigoriadis, Kristiana, primary, Huebner, Ariana, additional, Bunkum, Abigail, additional, Colliver, Emma, additional, Frankell, Alexander M., additional, Hill, Mark S., additional, Thol, Kerstin, additional, Birkbak, Nicolai J., additional, Swanton, Charles, additional, Zaccaria, Simone, additional, and McGranahan, Nicholas, additional
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- 2023
- Full Text
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29. MA12.08 Growth Pattern Evolution of Lung Adenocarcinoma from Primary Tumour to Metastasis in TRACERx
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Karasaki, T., primary, Moore, D.A., additional, Huebner, A., additional, Al Bakir, M., additional, Frankell, A.M., additional, Grigoriadis, K., additional, Watkins, T.B.K., additional, McGranahan, N., additional, Swanton, C., additional, and Jamal-Hanjani, M., additional
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- 2023
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30. 6O Insights into tumour dissemination and progression using longitudinal imaging and ctDNA in the TRACERx lung cancer study
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Liu, W.K., primary, Ding, B., additional, Hessey, S., additional, Ruiz, C. Martinez, additional, Kittel, J., additional, Lombardelli, C., additional, Lee, H., additional, Veiga, C., additional, Richard, C., additional, Huebner, A., additional, Hackshaw, A., additional, Abbosh, C.Z., additional, Frankell, A.M., additional, Royle, G., additional, Swanton, C., additional, and Jamal-Hanjani, M., additional
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- 2023
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31. Clonal Evolution in Healthy and Premalignant Tissues: Implications for Early Cancer Interception Strategies
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Jayant K. Rane, Alexander M. Frankell, Clare E. Weeden, and Charles Swanton
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Cancer Research ,Oncology - Abstract
Histologically normal human tissues accumulate significant mutational burden with age. The extent and spectra of mutagenesis are comparable both in rapidly proliferating and post-mitotic tissues and in stem cells compared with their differentiated progeny. Some of these mutations provide increased fitness, giving rise to clones which, at times, can replace the entire surface area of tissues. Compared with cancer, somatic mutations in histologically normal tissues are primarily single-nucleotide variations. Interestingly though, the presence of these mutations and positive clonal selection in isolation remains a poor indicator of potential future cancer transformation in solid tissues. Common clonally expanded mutations in histologically normal tissues also do not always represent the most frequent early mutations in cancers of corresponding tissues, indicating differences in selection pressures. Preliminary evidence implies that stroma and immune system co-evolve with age, which may impact selection dynamics. In this review, we will explore the mutational landscape of histologically normal and premalignant human somatic tissues in detail and discuss cell-intrinsic and environmental factors that can determine the fate of positively selected mutations within them. Precisely pinpointing these determinants of cancer transformation would aid development of early cancer interventional and prevention strategies.
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- 2023
32. Clonal Evolution in Healthy and Premalignant Tissues: Implications for Early Cancer Interception Strategies
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Rane, Jayant K., primary, Frankell, Alexander M., additional, Weeden, Clare E., additional, and Swanton, Charles, additional
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- 2023
- Full Text
- View/download PDF
33. Antibodies against endogenous retroviruses promote lung cancer immunotherapy
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Ng, Kevin W, Boumelha, Jesse, Enfield, Katey S S; https://orcid.org/0000-0002-4551-6073, Almagro, Jorge; https://orcid.org/0000-0002-0652-6447, Cha, Hongui, Pich, Oriol; https://orcid.org/0000-0002-1956-1882, Karasaki, Takahiro; https://orcid.org/0000-0001-6863-2360, Moore, David A, Salgado, Roberto; https://orcid.org/0000-0002-1110-3801, Sivakumar, Monica, Young, George; https://orcid.org/0000-0002-1203-588X, Molina-Arcas, Miriam; https://orcid.org/0000-0002-8176-8948, de Carné Trécesson, Sophie, Anastasiou, Panayiotis, Fendler, Annika, Au, Lewis, Shepherd, Scott T C, Martínez-Ruiz, Carlos, Puttick, Clare, Black, James R M, Watkins, Thomas B K, Kim, Hyemin, Shim, Seohee, Faulkner, Nikhil, Attig, Jan; https://orcid.org/0000-0002-2159-2880, Veeriah, Selvaraju, Magno, Neil, Ward, Sophia; https://orcid.org/0000-0002-6777-5279, Frankell, Alexander M; https://orcid.org/0000-0002-0341-7878, Al Bakir, Maise; https://orcid.org/0000-0002-0846-8332, et al, Boos, Laura Amanda, Ng, Kevin W, Boumelha, Jesse, Enfield, Katey S S; https://orcid.org/0000-0002-4551-6073, Almagro, Jorge; https://orcid.org/0000-0002-0652-6447, Cha, Hongui, Pich, Oriol; https://orcid.org/0000-0002-1956-1882, Karasaki, Takahiro; https://orcid.org/0000-0001-6863-2360, Moore, David A, Salgado, Roberto; https://orcid.org/0000-0002-1110-3801, Sivakumar, Monica, Young, George; https://orcid.org/0000-0002-1203-588X, Molina-Arcas, Miriam; https://orcid.org/0000-0002-8176-8948, de Carné Trécesson, Sophie, Anastasiou, Panayiotis, Fendler, Annika, Au, Lewis, Shepherd, Scott T C, Martínez-Ruiz, Carlos, Puttick, Clare, Black, James R M, Watkins, Thomas B K, Kim, Hyemin, Shim, Seohee, Faulkner, Nikhil, Attig, Jan; https://orcid.org/0000-0002-2159-2880, Veeriah, Selvaraju, Magno, Neil, Ward, Sophia; https://orcid.org/0000-0002-6777-5279, Frankell, Alexander M; https://orcid.org/0000-0002-0341-7878, Al Bakir, Maise; https://orcid.org/0000-0002-0846-8332, et al, and Boos, Laura Amanda
- Abstract
B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)$^{1,2}$. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive$^{1,2}$. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma$^{3}$. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.
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- 2023
34. The evolution of lung cancer and impact of subclonal selection in TRACERx
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Frankell, A.M., Dietzen, M., Al Bakir, M., Lim, E.L., Karasaki, T., Ward, S., Veeriah, S., Colliver, E., Huebner, A., Bunkum, A., Hill, M.S., Grigoriadis, K., Moore, D.A., Black, J.R.M., Liu, W.K., Thol, K., Pich, O., Watkins, T.B.K., Naceur-Lombardelli, C., Cook, D.E., Salgado, R., Wilson, G.A., Bailey, C., Angelova, M., Bentham, R., Martínez-Ruiz, C., Abbosh, C., Nicholson, A.G., Le Quesne, J., Biswas, D., Rosenthal, R., Puttick, C., Hessey, S., Lee, C., Prymas, P., Toncheva, A., Smith, J., Xing, W., Nicod, J., Price, G., Kerr, K.M., Naidu, B., Middleton, G., Blyth, K.G., Fennell, D.A., Forster, M.D., Lee, S.M., Falzon, M., Hewish, M., Shackcloth, M.J., Lim, E., Benafif, S., Russell, P., Boleti, E., Krebs, M.G., Lester, J.F., Papadatos-Pastos, D., Ahmad, T., Thakrar, R.M., Lawrence, D., Navani, N., Janes, S.M., Dive, C., Blackhall, F.H, Summers, Y., Cave, J., Marafioti, T., Herrero, J., Quezada, S.A., Peggs, K.S., Schwarz, R.F., Van Loo, P., Miedema, D.M., Birkbak, N.J., Hiley, C.T., Hackshaw, A., Zaccaria, S., Jamal-Hanjani, M., McGranahan, N., and Swanton, C.
- Subjects
Cancer Research - Abstract
Lung cancer is the leading cause of cancer-associated mortality worldwide. 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.
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- 2023
35. The evolution of lung cancer and impact of subclonal selection in TRACERx
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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
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- 2023
36. CONIPHER: a computational framework for scalable phylogenetic reconstruction with error correction
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Kristiana Grigoriadis, Ariana Huebner, Abigail Bunkum, Emma Colliver, Alexander M. Frankell, Mark S. Hill, Nicolai J. Birkbak, Charles Swanton, Simone Zaccaria, and Nicholas McGranahan
- Abstract
Intra-tumour heterogeneity provides the fuel for the evolution and selection of subclonal tumour cell populations. However, accurate inference of tumour subclonal architecture and reconstruction of tumour evolutionary history from bulk DNA sequencing data remains challenging. Sequencing and alignment artefacts cannot be distinguished from real cancer somatic mutations and errors in the identification of copy number alterations or complex evolutionary events (e.g. mutation losses) affect the estimated cellular prevalence of mutations, leading to errors in mutation clustering and phylogenetic reconstructions. In this paper we present a new computational framework, CONIPHER (COrrecting Noise In PHylogenetic Evaluation and Reconstruction), that accurately infers subclonal structure and phylogenetic relationships from multi-sample tumour sequencing, accounting for both copy number alterations and mutation errors. CONIPHER outperforms similar methods on simulated datasets, and in particular scales to a large number of tumour samples and clones. As such, CONIPHER enables automated phylogenetic analysis which can be effectively applied to large sequencing datasets generated with different technologies.
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- 2023
37. 11P Mapping the pattern and pace of tumour dissemination using longitudinal imaging and ctDNA in the TRACERx lung study
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Liu, W.K., primary, Ding, B., additional, Hessey, S., additional, Kittel, J., additional, Lombardelli, C., additional, Lee, H., additional, Veiga, C., additional, Huebner, A., additional, Hackshaw, A., additional, Abbosh, C.Z., additional, Frankell, A.M., additional, Royle, G., additional, Swanton, C., additional, and Jamal-Hanjani, M., additional
- Published
- 2022
- Full Text
- View/download PDF
38. MA19.10 The Tracerx 421 Cohort Provides Insights to Key Pathological Features of Lung Squamous Cell Cancer
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Cheung, A., Moore, D.A., Karasaki, T., Puttick, C., Grigoriadis, K., Enfield, K.S.S., Frankell, A.M., McGranahan, N., Jamal-Hanjani, M., and Swanton, C.
- Published
- 2024
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- View/download PDF
39. OA15.03 Clinicogenomic Landscape of Lymph Node Metastases in TRACERx
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Karasaki, T., Al Bakir, M., Huebner, A., Black, J.R.M., Abbosh, C., McGranahan, N., Frankell, A.M., Jamal-Hanjani, M., and Swanton, C.
- Published
- 2024
- Full Text
- View/download PDF
40. LBA9 Clinical insights from ultra-sensitive tumour-informed ctDNA tracking across the TRACERx cohort
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Black, J.R.M., Karasaki, T., Abbott, C., Boyle, S., Li, B., Al Bakir, M., Liu, W.K., Veeriah, S., Jamal-Hanjani, M., McGranahan, N., Frankell, A.M., Chen, R., and Swanton, C.
- Published
- 2024
- Full Text
- View/download PDF
41. cloneMap: a R package to visualise clonal heterogeneity
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Alexander M Frankell, Emma Colliver, Nicholas Mcgranahan, and Charles Swanton
- Abstract
Genomic evolution and clonal heterogeneity in the soma are widespread and are involved in various pathologies with devastating consequences to human health, most prominently in neoplasia. Tools to interrogate and visualise the diversity of clonal populations in malignant or non-malignant tissues are currently lacking. cloneMap is a tool to represent clonal heterogeneity in a sample or set of samples, accounting for the clone size and phylogenetic relationships between clones. We apply cloneMap to several publicly available cancer sequencing datasets to demonstrate its ability to provide biological inferences of clonal heterogeneity. cloneMap is an R package available on github (https://github.com/amf71/cloneMap).
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- 2022
42. When can we be confident of surgical cure with ctDNA?
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Alexander Frankell and Mariam Jamal-Hanjani
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Oncology ,Biomarkers, Tumor ,Humans ,Circulating Tumor DNA - Published
- 2022
43. Longitudinal tracking of 97 esophageal adenocarcinomas using liquid biopsy sampling
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J M J Weaver, N. Masque Soler, Christopher C.W. Hughes, Rebecca C. Fitzgerald, K Lehovsky, Elizabeth C Smyth, Nicola Grehan, E. Ococks, Ginny Devonshire, H. Coles, Alexander M. Frankell, A. Northrop, A. Redmond, Adrienn Blasko, and Barbara Nutzinger
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Esophageal Neoplasms ,medicine.medical_treatment ,Adenocarcinoma ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Peripheral blood cell ,Prospective Studies ,Liquid biopsy ,Survival rate ,Aged ,Chemotherapy ,business.industry ,Incidence (epidemiology) ,Hazard ratio ,Liquid Biopsy ,Cancer ,Hematology ,medicine.disease ,Confidence interval ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Neoplasm Recurrence, Local ,business - Abstract
The incidence of esophageal adenocarcinoma (EAC) is rapidly rising and has a 5-year survival rate of20%. Beyond TNM (tumor-node-metastasis) staging, no reliable risk stratification tools exist and no large-scale studies have profiled circulating tumor DNA (ctDNA) at relapse in EAC. Here we analyze the prognostic potential of ctDNA dynamics in EAC, taking into account clonal hematopoiesis with indeterminate potential (CHIP).A total of 245 samples from 97 patients treated with neoadjuvant chemotherapy and surgery were identified from the prospective national UK Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) consortium data set. A pan-cancer ctDNA panel comprising 77 genes was used. Plasma and peripheral blood cell samples were sequenced to a mean depth of 7082× (range 2196-28 524) and ctDNA results correlated with survival.Characteristics of the 97 patients identified were as follows: 83/97 (86%) male, median age 68 years (SD 9.5 years), 100% cT3/T4, 75% cN+. EAC-specific drivers had higher variant allele fractions than passenger mutations. Using stringent quality criteria 16/79 (20%) were ctDNA positive following resection; recurrence was observed in 12/16 (75%) of these. As much as 78/97 (80%) had CHIP analyses that enabled filtering for CHIP variants, which were found in 18/78 (23%) of cases. When CHIP was excluded, 10/63 (16%) patients were ctDNA positive and 9/10 of these (90%) recurred. With correction for CHIP, median cancer-specific survival for ctDNA-positive patients was 10.0 months versus 29.9 months for ctDNA-negative patients (hazard ratio 5.55, 95% confidence interval 2.42-12.71; P = 0.0003). Similar outcomes were observed for disease-free survival.We demonstrate in a large, national, prospectively collected data set that ctDNA in plasma following surgery for EAC is prognostic for relapse. Inclusion of peripheral blood cell samples can reduce or eliminate false positives from CHIP. In future, post-operative ctDNA could be used to risk stratify patients into high- and low-risk groups for intensification or de-escalation of adjuvant chemotherapy.
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- 2021
44. cloneMap: a R package to visualise clonal heterogeneity
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Frankell, Alexander M, primary, Colliver, Emma, additional, Mcgranahan, Nicholas, additional, and Swanton, Charles, additional
- Published
- 2022
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45. Abstract 645: Heterogeneity of immunotherapy biomarkers in the TRACERx non-small cell lung cancer multi-region lung cancer cohort study
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Hiley, Crispin T., primary, Litchfield, Kevin, additional, Pich, Oriol, additional, Moore, David, additional, Naceur-Lombardelli, Cristina, additional, Veeriah, Selvaraju, additional, Bakir, Maise Al, additional, Summan, Simranpreet, additional, Grigoriadis, Kristiana, additional, Ruiz, Carlos Martinez, additional, Puttick, Clare, additional, Enfield, Katey, additional, Ward, Sophia, additional, Frankell, Alexander, additional, Biswas, Dhruva, additional, Rosenthal, Rachel, additional, Birkbak, Nicolai J., additional, Jamal-Hanjani, Mariam, additional, McGranahan, Nicholas, additional, Swanton, Charles, additional, and Consortium, TRACERx, additional
- Published
- 2022
- Full Text
- View/download PDF
46. Abstract 1394: Pervasive allele specific transcriptional repression of the class I and II HLA genes in TRACERx non-small cell lung cancer
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Puttick, Clare, primary, Pich, Oriol, additional, Leung, Michelle, additional, Martinez-Ruiz, Carlos, additional, Bentham, Robert, additional, Rosenthal, Rachel, additional, Hessey, Sonya, additional, Black, James R., additional, Lim, Emilia L., additional, Enfield, Katey, additional, Colliver, Emma, additional, Dijkstra, Krijn, additional, Hiley, Crispin T., additional, Karasaki, Takahiro, additional, Huebner, Ariana, additional, Bakir, Maise Al, additional, Watkins, Thomas B., additional, Frankell, Alexander M., additional, Zaccaria, Simone, additional, Jamal-Hanjani, Mariam, additional, McGranahan, Nicholas, additional, and Swanton, Charles, additional
- Published
- 2022
- Full Text
- View/download PDF
47. Genetics and Biomarkers in Barrett’s Esophagus and Esophageal Adenocarcinoma
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Katz-Summercorn, Annalise C., primary, Frankell, Alexander M., additional, and Fitzgerald, Rebecca C., additional
- Published
- 2016
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48. List of Contributors
- Author
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Belghazi, Kamar, primary, Bergman, Jacques J., additional, Berzin, Tyler M., additional, Boom, Kathryn, additional, Chak, Amitabh, additional, Chuttani, Ram, additional, Çolak, Yaşar, additional, Dumot, John A., additional, Dunkin, Brian J., additional, Erim, Tolga, additional, Fitzgerald, Rebecca C., additional, Frankell, Alexander M., additional, Goetz, Martin, additional, Goldsmith, Jeffrey D., additional, Gora, Michalina J., additional, Higa, Jennifer T., additional, Hwang, Joo Ha, additional, Itzkan, Irving, additional, Katz-Summercorn, Annalise C., additional, Khan, Umar, additional, Kistangari, Gaurav, additional, Patil, Deepa T., additional, Perelman, Lev T., additional, Pleskow, Douglas K., additional, Podugu, Amareshwar, additional, Pouw, Roos E., additional, Qiu, Le, additional, Rau, Nikhiel B., additional, Sawhney, Mandeep, additional, Schneider, Alison, additional, Şenateş, Ebubekir, additional, Tearney, Guillermo J., additional, Thota, Prashanthi N., additional, Triadafilopoulos, George, additional, Turzhitsky, Vladimir, additional, Vitkin, Edward, additional, Wang, Fen, additional, Yee, Eric U., additional, and Zhang, Lei, additional
- Published
- 2016
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49. Allele-informed copy number evaluation of plasma DNA samples from metastatic prostate cancer patients: the PCF_SELECT consortium assay
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Orlando, Francesco, Romanel, Alessandro, Trujillo, Blanca, Sigouros, Michael, Wetterskog, Daniel, Quaini, Orsetta, Leone, Gianmarco, Xiang, Jenny Z, Wingate, Anna, Tagawa, Scott, Jayaram, Anuradha, Linch, Mark, Swanton, Charles, Jamal-Hanjani, Mariam, Abbosh, Chris, Zaccaria, Simone, Hessey, Sonya, Shiu, Kai-Keen, Bridgewater, John, Hochhauser, Daniel, Forster, Martin, Lee, Siow-Ming, Ahmad, Tanya, Papadatos-Pastos, Dionysis, Janes, Sam, Van Loo, Peter, Enfield, Katey, McGranahan, Nicholas, Huebner, Ariana, Quezada, Sergio, Beck, Stephan, Parker, Peter, Enver, Tariq, Hynds, Robert E, Dijkstra, Krijn, Pearce, David R, Falzon, Mary, Proctor, Ian, Sinclair, Ron, Lok, Chi-wah, Rhodes, Zoe, Moore, David, Marafioti, Teresa, Mitchison, Miriam, Ellery, Peter, Sivakumar, Monica, Brandner, Sebastian, Rowan, Andrew, Hiley, Crispin, Veeriah, Selvaraju, Shaw, Heather, Attard, Gert, Naceur-Lombardelli, Cristina, Toncheva, Antonia, Prymas, Paulina, Watkins, Tom, Bailey, Chris, Ruiz, Carlos Martinez, Litchfield, Kevin, Al-Bakir, Maise, Kanu, Nnenna, Ward, Sophie, Lim, Emilia, Reading, James, Chain, Benny, Alba, Blanca Trujillo, Akay, Melek, Flanagan, Adrienne, Biswas, Dhruva, Pich, Oriol, Dietzen, Michelle, Puttick, Clare, Colliver, Emma, Magness, Alistair, Angelova, Mihaela, Black, James, Lucas, Olivia, Hill, William, Liu, Wing-Kin, Frankell, Alexander, Magno, Neil, Athanasopoulou, Foteini, Wilson, Gareth, Rosenthal, Rachel, Salgado, Roberto, Lee, Claudia, Grigoriadis, Kristiana, Al-Sawaf, Othman, Karasaki, Takahiro, Bunkum, Abigail, Noorani, Imran, Benafif, Sarah, Barbe, Vittorio, Bola, Supreet, Vainauskas, Osvaldas, Hasan, Mahedi, Lise, Stefano, Leone, GianMarco, Alifrangis, Constantine, McGovern, Ursula, Thol, Kerstin, Gamble, Samuel, Ung, Seng Kuong, Sahwangarrom, Teerapon, Marin, Claudia Peinador, Wong, Sophia, Pawlik, Piotr, Gishen, Faye, Tookman, Adrian, Stone, Paddy, Stirling, Caroline, Turajlic, Samra, Larkin, James, Pickering, Lisa, Furness, Andrew, Young, Kate, Drake, Will, Edmonds, Kim, Hunter, Nikki, Mangwende, Mary, Pearce, Karla, Grostate, Lauren, Au, Lewis, Spain, Lavinia, Shepherd, Scott, Yan, Haixi, Shum, Ben, Tippu, Zayd, Hanley, Brian, Spencer, Charlotte, Emmerich, Max, Gerard, Camille, Schmitt, Andreas Michael, Del Rosario, Lyra, Carlyle, Eleanor, Lewis, Charlotte, Holt, Lucy, Lucanas, Analyn, O'Flaherty, Molly, Hazell, Steve, Mudhar, Hardeep, Messiou, Christina, Latifoltojar, Arash, Fendler, Annika, Byrne, Fiona, Pallinkonda, Husayn, Lobon, Irene, Coulton, Alex, Cattin, Anne Laure, Deng, Daqi, Feng, Geoffrey Hugang, Rowan, Andew, Yousaf, Nadia, Popat, Sanjay, Curtis, Olivia, Milner-Watts, Charlotte, Stamp, Gordon, Nye, Emma, Murra, Aida, Korteweg, Justine, Kelly, Denise, Terry, Lauren, Biano, Jennifer, Peat, Kema, Kelly, Kayleigh, Hill, Peter, Josephs, Debra, Irshad, Sheeba, Chandra, Ashish, Spicer, James, Mahadeva, Ula, Green, Anna, Stewart, Ruby, Iredale, Lara-Rose, Mackay, Tina, Deakin, Ben, Enting, Debra, Rudman, Sarah, Ghosh, Sharmistha, Karapagniotou, Lena, Pintus, Elias, Tutt, Andrew, Howlett, Sarah, Michalarea, Vasiliki, Brenton, James, Caldas, Carlos, Fitzgerald, Rebecca, Jimenez-Linan, Merche, Provenzano, Elena, Cluroe, Alison, Paterson, Anna, Aitken, Sarah, Allinson, Kieren, Stewart, Grant, McDermott, Ultan, Beddowes, Emma, Maughan, Tim, Ansorge, Olaf, Campbell, Peter, Roxburgh, Patricia, Fraser, Sioban, Kidd, Andrew, Blyth, Kevin, Le Quesne, John, Krebs, Matthew, Blackhall, Fiona, Summers, Yvonne, Oliveira, Pedro, Ortega-Franco, Ana, Dive, Caroline, Gomes, Fabio, Carter, Mat, Dransfield, Jo, Thomas, Anne, Fennell, Dean, Shaw, Jacqui, Naidu, Babu, Baijal, Shobhit, Tanchel, Bruce, Langman, Gerald, Robinson, Andrew, Collard, Martin, Cockcroft, Peter, Ferris, Charlotte, Bancroft, Hollie, Kerr, Amy, Middleton, Gary, Webb, Joanne, Kadiri, Salma, Colloby, Peter, Olisemeke, Bernard, Wilson, Rodelaine, Tomlinson, Ian, McNeish, Iain, Jogai, Sanjay, Holden, Samantha, Fernandes, Tania, Hampton, Blanche, McKenzie, Mairead, Hackshaw, Allan, Sharp, Abby, Chan, Kitty, Farrelly, Laura, Bridger, Hayley, Leslie, Rachel, Consortium, PEACE, Rubin, Mark A, Wyatt, Alexander W, Beltran, Himisha, Attard, Gerhardt, and Demichelis, Francesca
- Subjects
Chemical Biology & High Throughput ,Signalling & Oncogenes ,Human Biology & Physiology ,Ecology,Evolution & Ethology ,Genome Integrity & Repair ,Tumour Biology ,Genetics & Genomics ,Computational & Systems Biology - Abstract
Sequencing of cell-free DNA (cfDNA) in cancer patients’ plasma offers a minimally-invasive solution to detect tumor cell genomic alterations to aid real-time clinical decision-making. The reliability of copy number detection decreases at lower cfDNA tumor fractions, limiting utility at earlier stages of the disease. To test a novel strategy for detection of allelic imbalance, we developed a prostate cancer bespoke assay, PCF_SELECT, that includes an innovative sequencing panel covering ∼25 000 high minor allele frequency SNPs and tailored analytical solutions to enable allele-informed evaluation. First, we assessed it on plasma samples from 50 advanced prostate cancer patients. We then confirmed improved detection of genomic alterations in samples with
- Published
- 2022
- Full Text
- View/download PDF
50. 11P Mapping the pattern and pace of tumour dissemination using longitudinal imaging and ctDNA in the TRACERx lung study
- Author
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W.K. Liu, B. Ding, S. Hessey, J. Kittel, C. Lombardelli, H. Lee, C. Veiga, A. Huebner, A. Hackshaw, C.Z. Abbosh, A.M. Frankell, G. Royle, C. Swanton, and M. Jamal-Hanjani
- Subjects
Oncology ,Hematology - Published
- 2022
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